Dipeptide derivatives

ABSTRACT

This invention is directed to compounds of the formula                    
     and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis and/or frailty, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis and/or frailty when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of U.S. Ser. No. 09/380,887, filed Sep. 8, 199, nowU.S. Pat. No. 6,251,902, which is a 371 of PCT/IB98/008,731 filed Jun,5, 1998, entitled “Dipeptide Derivatives as Growth HormoneSecretagogues,” and claims benefit to U.S. Proviosional Application No.60/050,764, filed Jun. 25, 1997.

BACKGROUND OF THE INVENTION

Growth hormone (GH), which is secreted from the pituitary gland,stimulates growth of all tissues of the body that are capable ofgrowing. In addition, growth hormone is known to have the followingbasic effects on the metabolic processes of the body:

1. Increased rate of protein synthesis in substantially all cells of thebody;

2. Decreased rate of carbohydrate utilization in cells of the body; and

3. Increased mobilization of free fatty acids and use of fatty acids forenergy.

Deficiency in growth hormone results in a variety of medical disorders.In children, it causes dwarfism. In adults, the consequences of acquiredGH deficiency include profound reduction in lean body mass andconcomitant increase in total body fat, particularly in the truncalregion. Decreased skeletal and cardiac muscle mass and muscle strengthlead to a significant reduction in exercise capacity. Bone density isalso reduced. Administration of exogenous growth hormone has been shownto reverse many of the metabolic changes. Additional benefits of therapyhave included reduction in LDL cholesterol and improved psychologicalwell-being.

In cases where increased levels of growth hormone were desired, theproblem was generally solved by providing exogenous growth hormone or byadministering an agent which stimulated growth hormone production and/orrelease. In either case the peptidyl nature of the compound necessitatedthat it be administered by injection. Initially the source of growthhormone was the extraction of the pituitary glands of cadavers. Thisresulted in an expensive product, and carried with it the risk that adisease associated with the source of the pituitary gland could betransmitted to the recipient of the growth hormone (e.g.,Jacob-Creutzfeld disease). Recently, recombinant growth hormone hasbecome available which, while no longer carrying any risk of diseasetransmission, is still a very expensive product which must be given byinjection or nasal spray.

Most GH deficiencies are caused by defects in GH release, not primarydefects in pituitary synthesis of GH. Therefore, an alternative strategyfor normalizing serum GH levels is by stimulating its release fromsomatotrophs. Increasing GH secretion can be achieved by stimulating orinhibiting various neurotransmitter systems in the brain andhypothalamus. As a result, the development of synthetic growthhormone-releasing agents to stimulate pituitary GH secretion are beingpursued, and may have several advantages over expensive and inconvenientGH replacement therapy. By acting along physiologic regulatory pathways,the most desirable agents would stimulate pulsatile GH secretion, andexcessive levels of GH that have been associated with the undesirableside effects of exogenous GH administration would be avoided by virtueof intact negative feedback loops.

Physiologic and pharmacologic stimulators of GH secretion, which includearginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin,and insulin induced hypoglycemia, as well as activities such as sleepand exercise, indirectly cause growth hormone to be released from thepituitary by acting in some fashion on the hypothalamus perhaps eitherto decrease somatostatin secretion or to increase the secretion of theknown secretagogue growth hormone releasing factor (GHRF) or an unknownendogenous growth hormone-releasing hormone or all of these.

Obesity is a major risk factor for diabetes, and a large fraction ofNIDDM patients are obese. Both conditions are characterized by elevatedcirculating insulin levels and suppressed GH levels. GH treatment ofGH-deficient adults (Jorgensen, J. O. L., et al., Lancet 1:1221 (1989)),obese women (Richelsen, B., et al., Am J Physiol, 266:E211 (1994)) andelderly men (Rudman, D., et al, Horm Res 36 (Suppl 1):73 (1991)) hasbeen shown to produce increases in lean body, hepatic and muscle masswhile decreasing fat mass. Thus, GH therapy for obesity would seemattractive except for the diabetogenic effects of GH.

An alternative to exogenous GH administration is therapy that stimulatesendogenous GH secretion. It has been shown that a substantial pituitaryreserve of GH is present in pituitary-intact GH-deficient patients andthe elderly so that decreased serum GH levels are due to hyposecretion.

Hyposecretion of GH in several clinical settings (obesity, aging,glucocorticoid suppression) is relatively resistant to stimulation byGHRH (Gertz, B. J., et al., J Clin Endocrinol Metab, 79:745 (1994);Arvat, E., et al., J Clin Endocrinol Metab, 79:1440 (1994); Maccardo,M., et al., Metabolism, 44:134 (1995)). In contrast, administration of aGHRP or combined administration of GHRH and a GHRP in these patients canelicit a robust GH response (Aloi, J. A., et al., J Clin EndocrinolMetab, 79:943; (1994)). Single dose studies of GHRPs have demonstratedthe absence of an acute effect on circulating insulin or glucose levels.Insulin and glucose have generally not been monitored in chronic studiesexcept to document the absence of unfavorable changes (Jacks, T., etal., J Endocrinol. 143:399 (1993)).

Prior to the present invention, the use of GHRPs or GHRP mimetics toimprove glycemic control has not specifically been explored. The methodof treating insulin resistance in a mammal comprising the administrationof a compound of Formula I of this invention is practiced preferentiallyin patients who have a functional hypothalamic-pituitary axis capable ofGH secretory responses to GHRPs and who have pancreatic beta-cellscapable of secreting insulin.

Other compounds have been developed which stimulate the release ofendogenous growth hormone such as analogous peptidyl compounds relatedto GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, whileconsiderably smaller than growth hormones, are still susceptible tovarious proteases. As with most peptides, their potential for oralbioavailability is low.

WO 94/13696 refers to certain spiropiperidines and homologues whichpromote release of growth hormone. Preferred compounds described thereinare of the general structure shown below.

WO 94/11012 refers to certain dipeptides that promote release of growthhormone. These dipeptides have the general structure

where L is

The compounds of WO 94/11012 and WO 94/13696 are reported to be usefulin the treatment of osteoporosis in combination with parathyroid hormoneor a bisphosphonate.

PCT publication WO 97/09060 discloses the use of growth hormonereleasing hormone or a functional analog thereof in the treatment ofinsulin resistance in mammals.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula:

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug,

wherein

HET is a heterocyclic moiety selected from the group consisting of

d is 0, 1 or 2;

e is 1 or 2;

A is a divalent radical, where the left hand side of the radical asshown below is connected to C″ and the right hand side of the radical asshown below is connected to C′, selected from the group consisting of

—NR²—C(O)—NR²—,

—NR²—S(O)₂—NR²—,

—O—C(O)—NR²—,

—NR²—C(O)—O—,

—C(O)—NR²—C(O)—,

—C(O)—NR²—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—NR²—C(O)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—O—C(O)—,

—C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—,

—NR²—C(O)—C(R⁹R¹⁰)—,

—O—C(O)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(O)—NR²—,

—C(O)—NR²—C(O)—,

—C(R⁹R¹⁰)—C(O)—O—,

—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(O)—O—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R₁₀)—,

—S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—C(O)—,

—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—,

—C(R⁹R¹⁰)—NR²—C(O)—O—,

—C(R⁹R¹⁰)—O—C(O)—NR²,

—C(R⁹R¹⁰)—NR²—C(O)—NR²—,

—NR²—C(O)—O—C(R⁹R¹⁰)—,

—NR²—C(O)—NR²—C(R⁹R¹⁰)—,

—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—,

—O—C(O)—NR²—C(R⁹R¹⁰)—,

—C(O)—N═C(R¹¹)—NR²—,

—C(O)—NR²—C(R¹¹)═N—,

—C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—,

—NR¹²—C(R⁹R¹⁰)—,

—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—NR²—C(R¹¹)═N—C(O)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,

—C(R⁹R¹⁰)—NR¹²—,

—N═C(R¹¹)—NR²—C(O)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,

—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,

—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—,

—C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,

—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and

—C(R⁹R¹⁰)—NR²—S(O)₂—NR²—;

Q is a covalent bond or CH₂;

W is CH or N;

X is CR⁹R¹⁰, C═CH₂ or C═O;

Y is CR⁹R¹⁰, O or NR²;

Z is C═O, C═S or S(O)₂;

G¹ is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl,—CONH₂, —(C₁-C₄)alkyl optionally independently substituted with one ormore phenyl, one or more halogens or one or more hydroxy groups,—(C₁-C₄)alkoxy optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,—(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl, N,N-di-(C₁-C₄)alkylamino,—(C₂-C₆)alkenyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,—(C₂-C₆)alkynyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,—(C₃-C₆)cycloalkyl optionally independently substituted with one or more(C₁-C₄)alkyl groups, one or more halogens or one or more hydroxy groups,—(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G² and G³are each independently selected from the group consisting of hydrogen,halo, hydroxy, —(C₁-C₄)alkyl optionally independently substituted withone to three halo groups and —(C₁-C₄)alkoxy optionally independentlysubstituted with one to three halo groups;

R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(C)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

 Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—,—C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

 q is 0, 1, 2, 3 or 4;

 t is 0, 1, 2 or 3;

 said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹ areoptionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

R^(1A) is selected from the group consisting of hydrogen, F, Cl, Br, I,(C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl,thiazolyl(C₁-C₃)alkyl and thienyl(C₁-C₃)alkyl, provided that R^(1A) isnot F, Cl, Br or I when a heteroatom is vicinal to C″;

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

 where the alkyl groups and the cycloalkyl groups in the definition ofR² are optionally substituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2or 3 independently selected halo groups;

R³ is selected from the group consisting of A¹, (C₁-C₁₀)alkyl,—(C₁-C₆)alkyl-A¹, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl, —(C₁-C₅)alkyl-X¹—(C₀-C₅)alkyl-A¹ and—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

 where the alkyl groups in the definition of R³ are optionallysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5independently selected halo groups or 1, 2 or 3 independently selected—OX³ groups;

 X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C═C—;

R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isa bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴ and thenitrogen atom to which X⁴ is attached and the carbon atom to which R⁴ isattached and form a five to seven membered ring;

R⁶ is a bond or is

 where a and b are each independently 0, 1, 2 or 3;

 X⁵ and X^(5a) are each independently selected from the group consistingof hydrogen, CF₃, A¹ and optionally substituted (C₁-C₆)alkyl;

the optionally substituted (C₁-C₆)alkyl in the definition of X⁵ andX^(5a) is optionally substituted with a substituent selected from thegroup consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

 or the carbon bearing X⁵ or X^(5a) forms one or two alkylene bridgeswith the nitrogen atom bearing R⁷ and R⁸ wherein each alkylene bridgecontains 1 to 5 carbon atoms, provided that when one alkylene bridge isformed then only one of X⁵ or X^(5a) is on the carbon atom and only oneof R⁷ or R⁸ is on the nitrogen atom and further provided that when twoalkylene bridges are formed then X⁵ and X^(5a) cannot be on the carbonatom and R⁷ and R⁸ cannot be on the nitrogen atom;

 or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a partially saturated or fully saturated 3- to7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

 or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a bicyclic ring system consisting of a partiallysaturated or fully saturated 5- or 6-membered ring, optionally having 1or 2 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

 Z¹ is a bond, O or N—X², provided that when a and b are both 0 then Z¹is not N—X² or O;

R⁷ and R⁸ are each independently hydrogen or optionally substituted(C₁-C₆)alkyl;

 where the optionally substituted (C₁-C₆)alkyl in the definition of R⁷and R⁸ is optionally independently substituted with A¹,—C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groups or 1 to 3(C₁-C₆)alkoxy groups; or

R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

 where L is C(X²)(X²), S(O)_(m) or N(X²);

R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups;

R¹¹ is selected from the group consisting of (C₁-C₅)alkyl and phenyloptionally substituted with 1-3 substitutents each independentlyselected from the group consisting of (C₁-C₅)alkyl, halo and(C₁-C₅)alkoxy;

R¹² is selected from the group consisting of (C₁-C₅)alkylsulfonyl,(C₁-C₅)alkanoyl and (C₁-C₅)alkyl where the alkyl portion is optionallyindependently substituted by 1-5 halo groups;

A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

 A¹ for each occurrence is independently optionally substituted, on oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

 the optionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3(C₁-C₁₀)alkanoyloxy groups or 1 to 3 (C₁-C₆)alkoxy groups;

 X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl orthienyl, provided that when X¹² is not hydrogen, the X¹² group isoptionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

 or X¹¹ and X¹² are taken together to form —(CH₂)_(r)—L¹—(CH₂)_(r)—;

L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

r for each occurrence is independently 1, 2 or 3;

X² for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl or optionally substituted (C₃C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or1-3 OX³ groups;

X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

X⁶ for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optonallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and; together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member;

 X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with hydroxy;

m for each occurrence is independently 0, 1 or 2;

with the proviso that:

X⁶ and X¹² cannot be hydrogen when attached to C(O) or S(O)₂ in the formC(O)X⁶, C(O)X¹², S(O)₂X⁶ or S(O)₂X¹²; and

when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

From herein on, the word “compounds” includes a stereoisomeric mixturethereof, diastereomerically enriched, diastereomercally pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug unless otherwise more specifically stated.

A preferred group of the foregoing compounds, designated the A Groupcompounds, are those compounds of formula I wherein

R⁴ is hydrogen or methyl; X⁴ is hydrogen;

R⁶ is

 where Z¹ is a bond and a is 0 or 1; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen, CF₃,phenyl and optionally substituted (C₁-C₆)alkyl;

 where the optionally substituted (C₁-C₆)alkyl in the definition of X⁵and X^(5a) is optionally substituted with OX² or A¹;

where A¹ in the definition of X⁵ and X^(5a) is imidazolyl, phenyl,indolyl, p-hydroxyphenyl, (C₅-C₇)cycloalkyl, —S(O)_(m)(C₁-C₆)alkyl,—N(X²)(X²) or —C(O)N(X²)(X²);

R⁷ is hydrogen or (C₁-C₃)alkyl;

or X⁵ and R⁷ are taken together and form a (C₁-C₅)alkylene bridge; and

R⁸ is hydrogen or (C₁-C₃)alkyl optionally substituted with one or twohydroxy groups.

A group of compounds which is preferred among the A Group compounds,designated the B Group, are those compounds of the A Group wherein b is0; X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, (C₁-C₃)alkyl and hydroxy(C₁-C₃)alkyl; and

R³ is selected from the group consisting of thienyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, thiazolyl-CH₂—O—CH₂—, 1-indolyl-CH₂—,2-indolyl-CH₂—, 3-indolyl-CH₂—, 1-naphthyl-CH₂, 2-naphthyl-CH₂—,1-benzimidazolyl-CH₂—, 2-benzimidazolyl-CH₂—, phenyl-(C₁-C₄)alkyl,2-pyridyl-(C₁-C₄)alkyl-, 3-pyrdyl-(C₁-C₄)alkyl-,4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂, thienyl-(C₁-C₄)alkyl-,phenyl-(C₀-C₃)alkyl-O—CH₂—, phenyl-CH₂—O-phenyl-CH₂—, phenyl-O—CH₂CH₂—and 3-benzothienyl-CH₂—;

 where the aryl portion(s) of the groups defined for R³ are eachoptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

A group of compounds which is preferred among the B Group compounds,designated the C Group, are those compounds of the B Group wherein

R⁴ is hydrogen; a is 0;

X⁵ and X^(5a) are each independently selected from the group consistingof hydrogen, methyl or hydroxymethyl, provided that when X⁵ is hydrogenthen X^(5a) is not hydrogen;

R⁷ and R⁸ are each hydrogen; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,1-naphthyl-CH₂—, 2-naphthyl-CH₂—, phenyl-(C₁-C₄)alkyl-,2-pyridyl-(C₁-C₄)alkyl-, 3-pyridyl-(C₁-C₄)alkyl-,4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂—, thienyl-(C₂-C₄)alkyl-,phenyl-(C₀-C₃)alkyl-O—CH₂—, 3-benzothienyl-CH₂—, thienyl-CH₂—O—CH₂—,thiazolyl-CH₂—O—CH₂—, pyridyl-CH₂—O—CH₂— and phenyl-O—CH₂—CH₂—;

 where the aryl portion(s) of the groups defined for R³ are eachoptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

A group of compounds which is preferred among the C Group compounds,designated the D Group, are those compounds of the C Group wherein

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

 A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl or thienyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

 the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to 3 fluoroatoms;

 q is 1 or 2; t is 1 or 2;

R³ is phenyl-CH₂—O—CH₂—, phenyl-CH₂—S—CH₂—, pyridyl-CH₂—O—CH₂—,thienyl-CH₂—O—CH₂—, thiazolyl-CH₂—O—CH₂—, phenyl-(CH₂)₃— or3-indolyl-CH₂—;

where the carbon atom bearing the substituent R³ is of the(R)-configuration;

 where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃; and

X⁵ and X^(5a) are each methyl.

A group of compounds which is preferred among the D Group compounds,designated the E Group, are those compounds of the D Group wherein HETis

A group of compounds which is preferred among the E Group compounds,designated the F Group, are those compounds of the E Group wherein

Z is S(O)₂; Q is a covalent bond; X is CH₂; and

Y is CH₂ or NR²;

 R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

A group of compounds which is preferred among the F Group compounds,designated the G Group, are those compounds of the F Group wherein Y isCH₂.

A group of compounds which is preferred among the G Group compounds,designated the H Group, are those compounds of the G Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

A preferred compound of the H Group is the 3a(R,S),1(R) diastereomericmixture, the 3a(R),1(R) diastereomer or the 3a(S),1(R) diastereomer of2-amino-N-[2-(3a-benzyl-1,1-dioxo-hexahydro-1-thia-5,7a-diaza-inden-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the E Groupcompounds, designated the I Group, are those compounds of the E Groupwherein

Z is C═O; Q is a covalent bond; X is CH₂; and Y is NR²;

 R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

A group of compounds which is preferred among the I Group compounds,designated the J Group, are those compounds of the I Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃;

R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluorogroups; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

A preferred compound of the J Group is the 8a(R,S),1(R) diastereomericmixture, the 8a(R),1(R) diastereomer or the 8a(S),1(R) diastereomer of2-amino-N-[2-(8a-benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the E Groupcompounds, designated the K Group, are those compounds of the E Groupwherein Z is C═O; Q is a covalent bond; X is CH₂; and Y is O.

A group of compounds which is preferred among the K Group compounds,designated the L Group, are those compounds of the K Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

A group of compounds which is preferred among the L Group compounds,designated the M Group, are where the compound is the 8a(R,S),1(R)diastereomeric mixture, the 8a(R),1(R) diastereomer or the 8a(S),1(R)diastereomer of the compound selected from the group consisting of

2-amino-N-[2-(8a-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,

2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-thiazol-4-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamideand

2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-3-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the E Groupcompounds, designated the N Group, are those compounds of the E Groupwherein

Z is C═O or S(O)₂; Q is a covalent bond; X is C═O; and Y is NR²;

 R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

A group of compounds which is preferred among the N Group compounds,designated the O Group, are those compounds of the N Group wherein

Z is C═O; R¹ is —CH₂—A¹, where A¹ in the definition of R¹ is phenyl orpyridyl where said phenyl or pyridyl is optionally substituted with oneto three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and

R³ is phenyl-CH₂—O—CH₂—, pyridyl-CH₂—O—CH₂—, phenyl-(CH₂)—,3-indolyl-CH₂— or thiazolyl-CH₂—O—CH₂—, where the aryl portion of thegroups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.

A group of compounds which is preferred among the O Group compounds,designated the P Group, are those compounds of the O Group wherein R² ishydrogen or (C₁-C₃)alkyl where the alkyl group is optionally substitutedwith 1-3 fluoro groups.

A group of compounds which is preferred among the P Group compounds,designated the Q Group, are those compounds of the P Group wherein

R³ is phenyl-CH₂—O—CH₂— or phenyl-(CH₂)₃—, where the phenyl in thedefinition of R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.

A group of compounds which is preferred among the Q Group compounds,designated the R Group, are those compounds of the Q Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, 2-pyridyl, 3-pyridyl, optionallysubstituted with 1-3 fluoro groups or 1-3 Chloro groups;

R² is methyl or ethyl where the ethyl group is optionally substitutedwith 1-3 fluoro groups; and

R³ is phenyl-CH₂—O—CH₂—, where the phenyl is optionally substituted with1-3 fluoro groups, 1-3 Chloro groups or 1-2 CF₃ groups.

A preferred compound of the R Group is the 1(R),8a(R,S) diastereomericmixture, the 1(R),8a(R) diastereomer or the 1(R),8a(S) diastereomer of2-amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-pyridin-3-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

A group of compounds which is preferred among the R Group compounds,designated the S Group, are those compounds of the R Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl optionally substituted with 1-2 chlorogroups or 1-2 fluoro groups;

R² is methyl or —CH₂CF₃; and

R³ is phenyl-CH₂—O—CH₂—, optionally substituted with 1-3 fluoro groups,1-3 chloro groups or 1-2 CF₃ groups.

A group of compounds which is preferred among the S Group compounds,designated the T Group, are those compounds of the S Group where thecompound is selected from the group consisting of

2-amino-N-[2-(8a-(R,S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,

2-amino-N{1-(R)-benzyloxymethyl-2-[8a-(R,S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydroimidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamideand

2-amino-N-{2-[8a-(R,S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide.

The following compounds are particularly preferred of the T Groupcompounds:

2-amino-N-[2-(8a-(R)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;

2-amino-N-[2-(8a-(S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;

2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(R)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

2-amino-N-{2-[8a-(R)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide;and

2-amino-N-{2-[8a-(S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide.

Another group of compounds which is preferred among the R Groupcompounds, designated the U Group, are those compounds of the R Groupwherein

R¹ is —CH₂A¹ where A¹ is 2-pyridyl optionally substituted with 1-2chloro groups;

R² is methyl or —CH₂CF₃; and

R³ is phenyl-CH₂—O—CH₂, optionally substituted with 1-3 fluoro groups,1-3 chloro groups or 1-2 CF₃ groups.

A group of compounds which is preferred among the U Group compounds,designated the V Group, are those compounds of the U Group where thecompound is

2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,

2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,

2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,

2-amino-N-[2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamideor

2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

The following compounds are particularly preferred of the V Groupcompounds:

2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide;

2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide;

2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

2-amino-N-[2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide;

2-amino-N-[2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide;

2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;and

2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

Another group of compounds which is preferred among the E Groupcompounds, designated the W Group, are those compounds of the E Groupwherein

Z is C═O; Q is a covalent bond; X is C═O; and Y is CH₂.

A group of compounds which is preferred among the W Group compounds,designated the X Group, are those compounds of the W Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of fluoro, chloro,methyl, OCH₃, OCF₂H, OCF₃ and CF₃; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

A preferred compound of the X Group is the 1(R),8a(R,S) diastereomericmixture, the 1(R),8a(R) diastereomer or the 1(R),8a(S) diastereomer of2-amino-N-{1-benzyloxymethyl-2-[8a-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide.

Another group of compounds which is preferred among the D Groupcompounds, designated the Y Group, are those compounds of the D Groupwherein

HET is

 A group of compounds which is preferred among the Y Group compounds,designated the Z Group, are those compounds of the Y Group wherein

W is N; d is 1; e is 0 or 1;

R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups;

G¹ is hydrogen, halo, hydroxy, —(C₁-C₂)alkyl optionally independentlysubstituted with one to three halo groups or —(C₁-C₂)alkoxy optionallyindependently substituted with one to three halo groups;

G² is hydrogen, halo, hydroxy, —(C₁-C₂)alkyl optionally independentlysubstituted with one to three halo groups or —(C₁-C₂)alkoxy optionallyindependently substituted with one to three halo groups; and

G³ is hydrogen.

A group of compounds which is preferred among the Z Group compounds,designated the AA Group, are those compounds of the Z Group wherein

R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluorogroups;

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

G¹, G² and G³ are each independently hydrogen, Cl or F.

A preferred compound of the AA Group is2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-oxo-2-(9-oxo-1,2,4a,9-tetrahydro-4H-3,9a-diaza-fluoren-3-yl)-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the C Groupcompounds, designated the AB Group, are those compounds of the C Groupwherein

HET is

 A group of compounds which is preferred among the AB Group compounds,designated the AC Group, are those compounds of the AB Group wherein

X⁵ and X^(5a) are each methyl; d is 1; e is 1;

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

 A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl or thienyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

 the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to 3 fluorogroups;

 t is 1 or 2; q is 1 or 2; and

R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

A group of compounds which is preferred among the AC Group compounds,designated the AD Group, are those compounds of the AC Group wherein

R¹ is (C₁-C₆)alkyl optionally substituted with 1-3 fluoro groups;

R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluorogroups; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

A preferred compound of the AD Group is2-amino-N-[2-(2,3-dimethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the D Groupcompounds, designated the AE Group, are those compounds of the D Groupwherein

HET is

 A group of compounds which is preferred among the AE Group compounds,designated the AF Group, are those compounds of the AE Group wherein

A is —NR²—C(O)—O—; d is 1; e is 1;

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

 A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl or thienyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

 the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1-3 fluorogroups;

 t is 1 or 2; q is 1 or 2;

R^(1A) is hydrogen or methyl; and

R² is hydrogen, (C₁-C₅)alkyl, —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl or(C₁-C₂)alkyl-A¹, where

A¹ in the definition of R² is pyridyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1-3 fluoro groups.

A group of compounds which is preferred among the AF Group compounds,designated the AG Group, are those compounds of the AF Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃;

R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluorogroups;

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

R^(1A) is hydrogen.

A group of compounds which is preferred among the AG Group compounds,designated the AH Group, are those compounds of the AG Group where thecompound is the 3a(R,S)-7a(R,S) diastereomeric mixture, the 3a(R),7a(R)diastereomer, the 3a(S),7a(S) diastereomer, the 3a(R),7a(S) diastereomeror the 3a(S),7a(R) diastereomer of the compound selected from the groupconsisting of3a-7a-2-amino-N-[2-(3a-benzyl-2-oxo-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,3a-7a-2-amino-N-[1-(R)-benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-3-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,3a-7a-2-amino-N-[2-(3a-benzyl-3-methyl-2-oxo-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-propionamideand3a-7a-2-amino-N-[1-(R)-benzyloxymethyl-2-oxo-2-(2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the AE Groupcompounds, designated the AI Group, are those compounds of the AE Groupwherein

A is —C(O)—NR²—CH₂—, —C(O)—O—CH₂—, —C(O)—NR²—C(O)—, —CH₂NR¹²—CH₂— or—C(O)—NR²—CH₂—CH₂—;

d is 1; e is 1;

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

 A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl or thienyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

 the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1-3 fluorogroups;

 t is 1 or 2; q is 1 or 2;

R^(1A) is hydrogen or methyl; and

R² is hydrogen, (C₁-C₅)alkyl, —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1-3 fluoro groups.

A group of compounds which is preferred among the AI Group compounds,designated the AJ Group, are those compounds of the AI Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃;

R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluorogroups; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

R^(1A) is hydrogen.

A group of compounds which is preferred among the AJ Group compounds,designated the AK Group, are those compounds of the AJ Group where thecompound is selected from the group consisting of2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer orthe 3a(S),1(R) diastereomer of2-amino-N-[2-(3a-benzyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer orthe 3a(S),1(R) diastereomer of2-amino-N-[2-(3a-benzyl-3-oxo-hexahydro-furo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer orthe 3a(S),1(R) diastereomer ofN-[2-(2-acetyl-3a-benzyl-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-(1H-indol-2-ylmethyl)-2-oxo-ethyl]-2-amino-2-methyl-propionamideand the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R) diastereomeror the 8a(S),1(R) diastereomer of2-amino-N-[2-(8a-benzyl-7-methyl-8-oxo-octahydro-[2,7]naphthyridin-2-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred among the AE Groupcompounds, designated the AL Group, are those compounds of the AE Groupwherein

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

 A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl or thienyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

 the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, or 1-3 fluorogroups;

 t is 1 or 2; q is 1 or 2;

R^(1A) is hydrogen or methyl;

R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1-3 fluoro groups;

d is 1; e is 1; and

R⁹ and R¹⁰ are each hydrogen.

A group of compounds which is preferred among the AL Group compounds,designated the AM Group, are those compounds of the AL Group wherein

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃;

R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluorogroups; and

R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

R^(1A) is hydrogen.

Another group of compounds which is preferred among the C Groupcompounds, designated the AN Group, are those compounds of the C Groupwherein

HET is

 Z is C═O or S(O)₂; Q is a covalent bond; X is C═O; Y is NR²;

 R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; wherethe alkyl and cycloalkyl groups in the definition of R² are optionallysubstituted with 1, 2 or 3 fluoro groups;

R¹ is hydrogen; and

R³ is selected from the group consisting of phenyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, phenyl-(CH₂)₃—, 3-indolyl-CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

A group of compounds which is preferred among the AN Group compounds,designated the AO Group, are those compounds of the AN Group wherein Zis C═O; R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups.

A group of compounds which is preferred among the AO Group compounds,designated the AP Group, are those compounds of the AO Group wherein R³is selected from the group consisting of 3-indolyl-CH₂—, phenyl-(CH₂)₃—,phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where the aryl portion ofthe groups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.

A preferred compound of the AP Group is8a-(R,S)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

An even more preferred compound of the AP Group is8a-(R)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

Another more preferred compound of the AP Group is8a-(S)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

This invention also provides:

methods for increasing levels of endogenous growth hormone in a human orother animal such as especially dogs, cats and horses, which compriseadministering to such human or other animal an effective amount of acompound of Formula I;

pharmaceutical compositions which comprise a pharmaceutically acceptablecarrier and an effective amount of a compound of Formula I;

pharmaceutical compositions useful for increasing the endogenousproduction or release of growth hormone in a human or other animal whichcomprise a pharmaceutically acceptable carrier, an effective amount of acompound of Formula I and a growth hormone secretagogue selected fromthe group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormonereleasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof;

methods for treating or preventing osteoporosis and/or frailty whichcomprise administering to a human or other animal especially dogs, catsand horses, in need of such treatment or prevention an amount of acompound of Formula I which is effective in treating or preventingosteoporosis and/or frailty;

methods for treating or preventing diseases or conditions which may betreated or prevented by growth hormone which comprise administering to ahuman or other animal in need of such treatment or prevention an amountof a compound of Formula I which is effective in promoting release ofendogenous growth hormone;

preferred methods of the immediately foregoing methods is where thedisease or condition is congestive heart failure, frailty associatedwith aging or obesity;

preferred methods of the immediately foregoing methods is where thedisease or condition is congestive heart failure or frailty associatedwith aging;

methods for accelerating bone fracture repair, attenuating proteincatabolic response after a major operation, reducing cachexia andprotein loss due to chronic illness such as AIDS or cancer, acceleratingwound healing, or accelerating the recovery of bum patients or patientshaving undergone major surgery, which methods comprise administering toa mammal in need of such treatment an amount of a compound of Formula Iwhich is effective in promoting release of endogenous growth hormone;

preferred methods of the immediately foregoing methods is foraccelerating the recovery of patients having undergone major surgery orfor accelerating bone fracture repair;

methods for improving muscle strength, mobility, maintenance of skinthickness, metabolic homeostasis or renal homeostasis, which methodscomprise administering to a human or other animal in need of suchtreatment an amount of a compound of Formula I which is effective inpromoting release of endogenous growth hormone;

methods for the treatment or prevention of osteoporosis and/or frailtywhich comprises administering to a human or other animal especiallydogs, cats and horses, with osteoporosis and/or frailty effectiveamounts of a bisphosphonate compound and a compound of Formula I;

preferred methods of the immediately foregoing methods is where thebisphosphonate compound is alendronate or ibandronate;

methods for the treatment or prevention of osteoporosis and/or frailtywhich comprise administering to a human or other animal especially dogs,cats and horses, with osteoporosis and/or frailty effective amounts ofestrogen or Premarin® and a compound of Formula I and, optionally,progesterone;

methods for the treatment of osteoporosis and/or frailty which compriseadministering to a human or other animal especially dogs, cats andhorses, with osteoporosis and/or frailty effective amounts of calcitoninand a compound of Formula I;

methods to increase IGF-1 levels in a human or other animal especiallydogs, cats and horses, deficient in IGF-1 which comprise administeringto a human or other animal with IGF-1 deficiency a compound of FormulaI;

methods for the treatment of osteoporosis and/or frailty which comprisesadministering to a human or other animal especially dogs, cats andhorses, with osteoporosis and/or frailty effective amounts of anestrogen agonist or antagonist and a compound of Formula I;

preferred methods of the immediately foregoing methods is where theestrogen agonist or antagonist is tamoxifen, droloxifene, raloxifene,idoxifene,cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline.

methods for enhancing growth and improving carcass quality of an animalother than humans which comprise administering to said animal aneffective amount of a compound of Formula I;

methods for enhancing feed efficiency in an animal other than humanswhich comprise administering to said animal an effective amount of acompound of Formula I;

methods for increasing milk production in a female mammal which compriseadministering to said female mammal an effective amount of a compound ofFormula I;

methods for increasing piglet number, increasing pregnancy rate in sows,increasing viability of piglets, increasing weight of piglets orincreasing muscle fiber size in piglets which comprise administering toa sow or piglet an effective amount of a compound of Formula I;

methods for increasing muscle mass, which comprise administering to ahuman or other animal such as dogs, cats, horses, cattle, pigs,chickens, turkeys, sheep and fish, in need of such treatment an amountof a compound of Formula I;

methods for promoting growth in growth hormone deficient children whichcomprise administering to a growth hormone deficient child a compound ofFormula I;

methods for the treatment or prevention of congestive heart failure,obesity or frailty associated with aging, which comprise administeringto a human or other animal in need thereof effective amounts of afunctional somatostatin antagonist and a compound of Formula I;

preferred methods of the immediately foregoing methods is where thefunctional somatostatin antagonist is an alpha-2 adrenergic agonist andthe other animal is a dog, cat or a horse;

preferred methods of the immediately foregoing methods is where thealpha-2 adrenergic agonist is clonidine, xylazine or medetomidine.

methods for treating insulin resistance in a mammal, which comprisesadministering to said mammal an effective amount of a compound ofFormula I;

preferred methods of the immediately foregoing methods is where thecondition associated with insulin resistance is type I diabetes, type IIdiabetes, hyperglycemia, impaired glucose tolerance or an insulinresistant syndrome; or where the condition associated with insulinresistance is associated with obesity or old age;

methods for increasing the endogenous production or release of growthhormone in a human or other animal especially dogs, cats and horses,which comprise administering effective amounts of a compound of FormulaI and a growth hormone secretagogue selected from the group consistingof GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF),IGF-1, IGF-2 and B-HT920 or an analog thereof;

pharmaceutical compositions useful for treating or preventingosteoporosis and/or frailty which comprise a pharmaceutically acceptablecarrier, an amount of a bisphosphonate compound and an amount of acompound of Formula I;

pharmaceutical compositions useful for treating or preventingosteoporosis and/or frailty which comprises a pharmaceuticallyacceptable carrier, an amount of estrogen or Premarin®, an amount of acompound of Formula I and, optionally, an amount of progesterone;

pharmaceutical compositions useful for treating osteoporosis and/orfrailty which comprise a pharmaceutically acceptable carrier, an amountof calcitonin and an amount of a compound of Formula I;

pharmaceutical compositions useful for treating preventing congestiveheart failure, obesity or frailty associated with aging, which comprisea pharmaceutically acceptable carrier, an amount of an alpha-2adrenergic agonist and an amount of a compound of Formula I;

a preferred pharmaceutical composition of the immediately foregoingcompositions is where the alpha-2 adrenergic agonist is clonidine,xylazine or medetomidine; and

methods for increasing levels of endogenous growth hormone, whichcomprise administering to a human or other animal in need thereofeffective amounts of a functional somatostatin antagonist and a compoundof Formula I.

In yet another aspect, this invention provides methods for improvingmuscle strength, mobility, maintenance of skin thickness, metabolichomeostasis and renal homeostasis, which comprise administering to ahuman or other animal especially dogs, cats and horses, in need of suchtreatment an amount of a compound of claim 1 which is effective inpromoting release of endogenous growth hormone.

The instant compounds promote the release of growth hormone which arestable under various physiological conditions and may be administeredparenterally, nasally or by the oral route.

Another group of compounds which is preferred within the E Groupcompounds, designated the EA Group, comprises those compounds, orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

Z is C═O; Q is a covalent bond;

Y is CR⁹R¹⁰

 where R⁹ in the definition of Y is selected from the group consistingof hydrogen, fluoro, hydroxy and (C₁-C₂)alkyl optionally substitutedwith 1-3 fluoro groups; and R¹⁰ in the definition of Y is selected fromthe group consisting of hydrogen, fluoro, and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups with the proviso that R¹⁰ cannot befluoro when R⁹ is hydroxy;

and X is CHR⁹

 where R⁹ in the definition of X is selected from the group consistingof hydrogen, fluoro, hydroxy and (C₁-C₂)alkyl optionally substitutedwith 1-3 fluoro groups.

A group of compounds which is preferred within the EA Group compounds,designated the EB Group, comprises those compounds or stereoisomericmixtures thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomers thereof, orprodrugs of such compounds, mixtures or isomers thereof, orpharmaceutically acceptable salts of the compounds, mixtures, isomers orprodrugs wherein:

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃; and

R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃.

A group of compounds which is preferred within the EB Group compounds,designated the EC Group, comprises those compounds or stereoisomericmixtures thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomers thereof, orprodrugs of such compounds, mixtures or isomers thereof, orpharmaceutically acceptable salts of the compounds, mixtures, isomers orprodrugs wherein

X is CH₂;

Y is CR⁹R¹⁰

 where R⁹ and R¹⁰ in the definition of Y are independently selected fromthe group consisting of hydrogen, fluoro, and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups.

A group of compounds which is preferred within the EC Group, designatedthe ED Group, comprises those compounds or prodrugs of such compounds orpharmaceutically acceptable salts of the compounds or prodrugs whereinthe compound is the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R)diastereomer or the 8a(S),1(R) diastereomer of2-amino-N-[2-(8a-benzyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamideor2-amino-N-[1-benzyloxymethyl-2-oxo-2-(6oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred within the J Groupcomprises those compounds or prodrugs of such compounds orpharmaceutically acceptable salts of the compounds or prodrugs whereinthe compound is the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R)diastereomer or the 8a(S),1(R) diastereomer of2-amino-N-{1-benzyloxymethyl-2-oxo-2-[3-oxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-ethyl}-2-methyl-propionamide;2-amino-N-{-1-benzyloxymethyl-2-[8a-(2,4-difluoro-benzyl)-3-oxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide;or2-amino-N-[1-benzyloxymethyl-2-(2-ethyl-3-oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

Another group of compounds which is preferred within the Q Groupcompounds, designated the QA Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

R¹ is —CH₂—A¹ where A¹ is phenyl, 2-pyridyl, or 3-pyridyl, optionallysubstituted with 1-3 F, 1-3 Cl;

R² is methyl or ethyl where the ethyl group is optionally substitutedwith 1-3 F; and

R³ is phenyl-(CH₂)₃—, where the phenyl is optionally substituted with1-3 F, 1-3 Cl or 1-2 CF₃;

A group of compounds which is preferred within the QA Group ofcompounds, designated the QB Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein R¹ is —(CH₂)—A¹ where A¹ is2-pyridyl, optionally substituted with 1-2 Cl; and R² is methyl or—CH₂CF₃.

A group of compounds which is preferred within the QB Group of:compounds, designated the QC Group, comprises those compounds orprodrugs of such compounds or pharmaceutically acceptable salts of thecompounds or prodrugs wherein the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.

An especially preferred compound within the QC Group comprises thecompound or prodrugs of such compound or pharmaceutically acceptablesalts of the compound or prodrugs where the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.

Another especially preferred compound within the QC Group comprises thecompound or prodrugs of such compound or pharmaceutically acceptablesalts of the compound or prodrugs where the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.

Another group of compounds which is preferred within the AI Group ofcompounds, designated the AI^(A) Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

A is —C(O)—NR²—CH₂—;

R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃;

R² is hydrogen or —(C₁-C₃)alkyl or —(C₀-C₂)alkyl-(C₃-C₅)cycloalkyl wherethe alkyl and cycloalkyl groups in the definition of R² are optionallysubstituted with 1-3 fluoro groups;

R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and

R^(1A) is hydrogen.

A group of compounds which is preferred within the AI^(A) Group ofcompounds, designated the AI^(B) Group, comprises those compounds orprodrugs of such compounds or pharmaceutically acceptable salts of thecompounds or prodrugs where the compound is the 3a(R,S),7a(R,S)diastereomeric mixture, the 3a(R),7a(R) diastereomer, the 3a(S),7a(S)diastereomer, the 3a(R),7a(S) diastereomer, or the 3a(S),7a(R)diastereomer of2-amino-N-[2-(3a-benzyl-2-cyclopropyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;or2-amino-N-[1(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-pyridin-2-ylmethyl-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide.

This invention also provides compounds of the formula

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug,

wherein

HET is a heterocyclic moiety selected from the group consisting of

d is 0, 1 or 2;

e is 1 or 2;

A is a divalent radical, where the left hand side of the radical asshown below is connected to C″ and the right hand side of the radical asshown below is connected to C′, selected from the group consisting of

—C(R⁹R¹⁰)—NR²—C(O)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—O—C(O)—,

—C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—,

—NR²—C(O)—C(R⁹R¹⁰)—,

—O—C(O)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(O)—NR²—,

—C(R⁹R¹⁰)—C(O)—O—,

—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(O)—O—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—C(O)—,

—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—,

—C(R⁹R¹⁰)—NR²—C(O)—O—,

—C(R⁹R¹⁰)—O—C(O)—NR²,

—C(R⁹R¹⁰)—NR²C(O)—NR²—,

—NR²—C(O)—O—C(R⁹R¹⁰)—,

—NR²—C(O)—NR²—C(R⁹R¹⁰)—,

—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—,

—O—C(O)—NR²—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—NR²—C(R⁹R¹⁰)—,

—NR¹²—C(R⁹R¹⁰)—,

—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,

—C(R⁹R¹⁰)—NR¹²—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)NR²—S(O)₂—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,

—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,

—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

—C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—,

—C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,

—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and

—C(R⁹R¹⁰)—NR²—S(O)₂—NR²—;

Q is a covalent bond or CH₂;

W is CH or N;

X is CR^(9a)R^(10a), C═CH₂ or C═O;

Y is CR⁹R¹⁰, O or NR²;

Z is C═O, C═S or S(O)₂;

R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,

—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,

—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹,

—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶,

—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶),

—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,

—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹,

—(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl,—(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,

(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

 Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—,—C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

 q is 0, 1, 2, 3 or 4;

 t is 0, 1, 2 or 3;

 said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹ areoptionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

R^(1A) is selected from the group consisting of hydrogen, F, Cl, Br, I,(C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl,thiazolyl(C₁-C₃)alkyl and thienyl(C₁-C₃)alkyl, provided that R^(1A) isnot F, Cl, Br or I when a heteroatom is vicinal to C″;

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

 where the alkyl groups and the cycloalkyl groups in the definition ofR² are optionally substituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2or 3 independently selected halo groups;

R³ is selected from the group consisting of A¹, (C₁-C₁₀)alkyl,—(C₁-C₆)alkyl-A¹, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl, —(C₁-C₅)alkyl-X¹—(C₀-C₅)-alkyl-A¹ and—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

 where the alkyl groups in the definition of R³ are optionallysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5independently selected halo groups or 1, 2 or 3 independently selected—OX³ groups;

 X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—;

R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and a the carbon atom to which they are attached andform (C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated orfully saturated 4- to 8-membered ring having 1 to 4 heteroatomsindependently selected from the group consisting of oxygen, sulfur andnitrogen, or is a bicyclic ring system consisting of a partiallysaturated or fully saturated 5- or 6-membered ring, fused to a partiallysaturated, fully unsaturated or fully saturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen;

X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴ and thenitrogen atom to which X⁴ is attached and the carbon atom to which R⁴ isattached and form a five to seven membered ring;

R⁶ is a bond or is

 where a and b are each independently 0, 1, 2 or 3;

X⁵ and X^(5a) are each independently selected from the group consistingof hydrogen, CF₃, A¹ and optionally substituted (C₁-C₆)alkyl;

the optionally substituted (C₁-C₆)alkyl in the definition of X⁵ andX^(5a) is optionally substituted with a substituent selected from thegroup consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

 or the carbon bearing X⁵ or X^(5a) forms one or two alkylene bridgeswith the nitrogen atom bearing R⁷ and R⁸ wherein each alkylene bridgecontains 1 to 5 carbon atoms, provided that when one alkylene bridge isformed then only one of X⁵ or X^(5a) is on the carbon atom and only oneof R⁷ or R⁸ is on the nitrogen atom and further provided that when twoalkylene bridges are formed then X⁵ and X^(5a) cannot be on the carbonatom and R⁷ and R⁸ cannot be on the nitrogen atom;

 or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a partially saturated or fully saturated 3- to7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

 or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a bicyclic ring system consisting of a partiallysaturated or fully saturated 5- or 6-membered ring, optionally having 1or 2 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

 Z¹ is a bond, O or N—X², provided that when a and b are both 0 then Z¹is not N—X² or O;

R⁷ and R⁸ are each independently hydrogen or optionally substituted(C₁-C₆)alkyl;

 where the optionally substituted (C₁-C₆)alkyl in the definition of R⁷and R⁸ is optionally independently substituted with A¹,—C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groups or 1 to 3(C₁-C₆)alkoxy groups; or

R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

 where L is C(X²)(X²), S(O)_(m) or N(X²);

R⁹, R^(9a), R¹⁰ and R^(10a) are each independently hydrogen, fluoro,hydroxy, (C₁-C₄)alkoxy or (C₁-C₅)alkyl optionally substituted with 1 to5 halogroups, provided that at least one of R⁹, R^(9a), R¹⁰ or R^(10a)is present and is (C₁-C;₄)alkoxy;

R¹¹ is selected from the group consisting of (C₁-C₅)alkyl and phenyloptionally substituted with 1-3 substitutents each independentlyselected from the group consisting of (C₁-C₅)alkyl, halo and(C₁-C₅)alkoxy;

R¹² is selected from the group consisting of (C₁-C₅)alkylsulfonyl,(C₁-C₅)alkanoyl and (C₁-C₅)alkyl where the alkyl portion is optionallyindependently substituted by 1-5 halo groups;

A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

 A¹ for each occurrence is independently optionally substituted, on oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

 the optionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3(C₁-C₁₀)alkanoyloxy groups or 1 to 3 (C₁-C₆)alkoxy groups;

X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl orthienyl, provided that when X¹² is not hydrogen, the X¹² group isoptionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

or X¹¹ and X¹² are taken together to form —(CH₂)_(r)—L¹—(CH₂)_(r)—;

 L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

r for each occurrence is independently 1, 2 or 3;

X² for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with -S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or1-3 OX³ groups;

X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

X⁶ for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or

when there are two X⁶ groups on one atom and both X⁶ are independently(C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may be optionally joined and,together with the atom to which the two X⁶ groups are attached, form a4- to 9-membered ring optionally having oxygen, sulfur or NX⁷ as a ringmember,

 X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with hydroxy;

m for each occurrence is independently 0, 1 or 2;

with the proviso that:

X⁶ and X¹² cannot be hydrogen when attached to C(O) or S(O)₂ in the formC(O)X⁶, C(O)X¹², S(O)₂X⁶ or S(O)₂X¹²; and

when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

A preferred group of compounds within the scope of the compoundsdisclosed in the immediately preceding paragraph, designated the ZAGroup, comprises those compounds or a stereoisomeric mixtures thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers thereof, or prodrugs of suchcompounds, mixtures or isomers thereof, or pharmaceutically acceptablesalts of the compounds, mixtures, isomers or prodrugs wherein:

HET is

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

 where A¹ in the definition or R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

 the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to 3 fluoroatoms;

 q is 1 or 2;

 t is 1 or 2;

R³ is selected form the group consisting of phenyl-CH₂—O—CH₂,phenyl-CH₂—S—CH₂—, pyridyl-CH₂—O—CH₂—, thienyl-CH₂—O—CH₂—,3-indolyl-CH₂—, phenyl-(CH₂)₃— and thiazolyl-CH₂—O—CH₂—; where thecarbon atom bearing the substituent R³ is of the (R)-configuration;

 where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃

R⁴ is hydrogen;

R⁶ is

 where Z¹ is a bond; X⁵ and X^(5a) are each methyl; a and b are each 0;

R⁷ and R⁸ or each hydrogen;

X⁴ is hydrogen.

A group of compounds which is preferred within the ZA Group ofcompounds, designated the ZB Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

Z is C═O; Q is a covalent bond;

Y is CR⁹R¹⁰

 where R⁹ in the definition of Y is selected from the group consistingof hydrogen, fluoro, hydroxy, (C₁-C₂)alkoxy and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups; and R¹⁰ in the definition of Y isselected from the group consisting of hydrogen, fluoro, and (C₁-C₂)alkyloptionally substituted with 1-3 fluoro groups with the proviso that R¹⁰cannot be fluoro when R⁹ is hydroxy or (C₁-C₂)alkoxy;

and X is CHR^(9a)

 where R⁹ in the definition of X is selected from the group consistingof hydrogen, fluoro, hydroxy, (C₁-C₂)alkoxy and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups.

R¹ is —CH₂—A¹

 where A¹ is phenyl, pyridyl or thiazolyl, optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and

R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—,

 where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃.

A group of compounds which is preferred within the ZB Group ofcompounds, designated the ZC Group, comprises those compounds orprodrugs of such compounds or pharmaceutically acceptable salts of thecompounds or prodrugs where the compound is the 8(R,S),8a(R,S)diastereomeric mixture, the 8(R),8a(R) diastereomer, the 8(S),8a(S)diastereomer, the 8(R),8a(S) diastereomer, or the 8(S),8a(R)diastereomer of2-amino-N-[1(R)-benzyloxymethyl-2-(8-methoxy-6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-2-oxo-ethyl]-2-methyl-propionamide.

This invention also provides methods of treating or preventing sleepdisorders in a mammal, including humans or other animals such asespecially dogs, cats and horses, which comprise administering to suchhuman or other animal an effective amount of a compound of Formula I.

This invention also provides the L-tartrate salt of2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

This invention also provides compounds of the formula

where R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X^(6), —(CH)₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

 where the alkyl and cycloalkyl groups in the definition of R¹ areoptonally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

 Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—,—C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

 m for each occurrence is 0, 1 or 2;

 q is 0, 1, 2, 3 or 4;

 t is 0, 1, 2 or 3;

 said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹ areoptionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

 A¹ for each occurrence is independently optionally substituted, on oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

 the optionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3(C₁-C₁₀)alkanoyloxy groups or 1 to 3 (C₁-C₆)alkoxy groups;

 X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl orthienyl, provided that when X¹² is not hydrogen, the X¹² group isoptionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

 or X¹¹ and X¹² are taken together to form —(CH₂)_(r)—L¹—(CH₂)_(t)—;

L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

X⁶ for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,

—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; and

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

 where the alkyl groups and the cycloalkyl groups in the definition ofR² are optionally substituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2or 3 independently selected halo groups.

A group of compounds which is preferred within the compounds disclosedwithin the immediately preceding paragraph, designated the XA Group,comprises those compounds wherein R¹ is CH₂—A¹ and R² is CF₃CH₂—.

A group of compounds which is preferred within the XA Group ofcompounds, designated the XB Group, comprises those compounds wherein A¹is 2-pyridyl.

A compound which is preferred within the XB Group of compounds is8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione.

Another compound which is preferred within the XB group of compounds isthe L-tartrate salt of8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione.

This invention also provides a process for preparing1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester comprising reacting8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dionewith D-tartaric acid in a reaction inert solvent at 0° C. to about roomtemperature for about 5 minutes to about 48 hours.

This invention also provides a process for preparing2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propionamidehydrochloride comprising

(a) reacting8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dionewith D-tartaric acid in a reaction inert solvent to form1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester;

(b) reacting said1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester with3-benyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid in the presence of a tertiary amine and 1-propanephosphonic acidcyclic anhydride in a reaction inert solvent to form(1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester, and

(c) reacting said(1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester with concentrated hydrochloric acid in a reactioninert solvent to form2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propionamidehydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

In general the compounds of Formula I can be made by processes known inthe chemical arts. Certain processes for the manufacture of Formula Icompounds are provided as further features of the invention and areillustrated by the following reaction schemes.

In the above structural formulae and throughout the instant application,the following terms have the indicated meanings unless expressly statedotherwise:

The alkyl groups are intended to include. those alkyl groups of thedesignated length in either a straight or branched configuration whichmay optionally contain double or triple bonds. Exemplary of such alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiarybutyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl,butadienyl, hexenyl and the like.

When the definition C₀-alkyl occurs in the definition, it means a singlecovalent bond.

The alkoxy groups specified above are intended to include those alkoxygroups of the designated length in either a straight or branchedconfiguration which may optionally contain double or triple bonds.Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy,hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxyand the like.

The term “halogen” or “halo” is intended to include the halogen atomsfluorine, chlorine, bromine and iodine.

The term “halogenated alkyl” is intended to include an alkyl group asdefined hereinabove substituted by one or more halogen atoms as definedhereinabove.

The term “halogenated cycloalkyl” is intended to include a cycloalkylgroup substituted by one or more halogen atoms as defined hereinabove.

The term “aryl” is intended to include phenyl and naphthyl and aromatic5- and 6-membered rings with 1 to 4 heteroatoms or fused 5- and/or6-membered bicyclic rings with 1 to 4 heteroatoms of nitrogen, sulfur oroxygen. Examples of such heterocyclic aromatic rings are pyridine,thiophene (also known as thienyl), furan, benzothiophene, tetrazole,indole, N-methylindole, dihydroindole, indazole, N-formylindole,benzimidazole, thiazole, pyrimidine, and thiadiazole.

The expression “prodrug” refers to compounds that are drug precursorswhich following administration, release the drug in vivo via somechemical or physiological process (e.g., a prodrug on being brought tothe physiological pH is converted to the desired drug form). Exemplaryprodrugs upon cleavage release the corresponding free acid, and suchhydrolyzable ester-forming residues of the compounds of this inventioninclude but are not limited to carboxylic acid substituents (e.g., whenR¹ is —(CH₂)_(q)C(O)OX⁶ where X⁶ is hydrogen, or when R² or A¹ containscarboxylic acid) wherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary prodrugs release an alcohol of Formula I wherein thefree hydrogen of the hydroxyl substituent (e.g., when R¹ containshydroxyl) is replaced by (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alka-noyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxy-carbonylamino-methyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacetyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacylmoieties are independently any of the naturally occurring L-amino acidsfound in proteins, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (theradical resulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

Prodrugs of this invention where a carboxyl group in a carboxylic acidof Formula I is replaced by an ester may be prepared by combining thecarboxylic acid with the appropriate alkyl halide in the presence of abase such as potassium carbonate in an inert solvent such as DMF at atemperature of about 0° C. to 100° C. for about 1 to about 24 hours.Alternatively, the acid is combined with the appropriate alcohol assolvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20° C. to 120° C.,preferably at reflux, for about 1 hour to about 24 hours. Another methodis the reaction of the acid in an inert solvent such as THF, withconcomitant removal of the water being produced by physical (e.g., DeanStark trap) or chemical (e.g., molecular sieves) means.

Prodrugs of this invention where an alcohol function has beenderivatized as an ether may be prepared by combining the alcohol withthe appropriate alkyl bromide or iodide in the presence of a base suchas potassium carbonate in an inert solvent such as DMF at a temperatureof about 0° C. to 1000° C. for about 1 to about 24 hours.Alkanoylaminomethyl ethers may be obtained by reaction of the alcoholwith a bis-(alkanoylamino)methane in the presence of a catalytic amountof acid in an inert solvent such as THF, according to a method describedin U.S. Pat. No. 4,997,984. Alternatively, these compounds may beprepared by the methods described by Hoffman et al. in J. Org. Chem.1994, 59, p. 3530.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other.

The compounds of the instant invention all have at least one asymmetriccenter as noted by the asterisk in the structural Formula I. Additionalasymmetric centers may be present on the molecule depending upon thenature of the various substituents on the molecule. Each such asymmetriccenter will produce two optical isomers and it is intended that all suchoptical isomers, as separated, pure or partially purified opticalisomers, racemic mixtures or diastereomeric mixtures thereof, beincluded within the scope of the instant invention. In the case of theasymmetric center represented by the asterisk, it has been found thatthe absolute stereochemistry of the more active and thus more preferredisomer is shown in Formula IA. This preferred absolute configurationalso applies to Formula I.

With the R⁴ substituent as hydrogen, the spatial configuration of theasymmetric center corresponds to that in a D-amino acid. In most casesthis is also designated an R-configuration although this will varyaccording to the values of R³ and R⁴ used in making R- orS-stereochemical assignments.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric,malonic, methane sulfonic and the like. In addition, certain compoundscontaining an acidic function such as a carboxy can be isolated in theform of their inorganic salt in which the counter-ion can be selectedfrom sodium, potassium, lithium, calcium, magnesium and the like, aswell as from organic bases.

The pharmaceutically acceptable salts are formed by taking about 1equivalent of a compound of Formula I and contacting it with about 1equivalent of the appropriate corresponding acid of the salt which isdesired. Work-up and isolation of the resulting salt is well-known tothose of ordinary skill in the art.

The growth hormone releasing compounds of Formula I are useful in vitroas unique tools for understanding how growth hormone secretion isregulated at the pituitary level. This includes use in the evaluation ofmany factors thought or known to influence growth hormone secretion suchas age, sex, nutritional factors, glucose, amino acids, fatty acids, aswell as fasting and non-fasting states. In addition, the compounds ofthis invention can be used in the evaluation of how other hormonesmodify growth hormone releasing activity. For example, it has alreadybeen established that somatostatin inhibits growth hormone release.

The compounds of Formula I can be administered to animals, includinghumans, to release growth hormone in vivo. The compounds are useful fortreating symptoms related to GH deficiency; stimulating pre- andpost-natal growth or enhancing feed efficiency and improving carcassquality of animals raised for meat production; increasing milkproduction in dairy cattle; improving estrous synchronization inlivestock such as swine, beef and dairy cattle; improving bone or woundhealing and improving vital organ function in animals. The compounds ofthe present invention, by inducing endogenous GH secretion, will alterbody composition and modify other GH-dependent metabolic, immunologic ordevelopmental processes. For example, the compounds of the presentinvention can be given to chickens, turkeys, livestock animals (such assheep, pigs, horses, cattle, etc.) and companion animals (e.g., dogs).These compounds may also have utility in aquaculture to accelerategrowth and improve the percent lean meat. In addition, these compoundscan be administered to humans in vivo as a diagnostic tool to directlydetermine whether the pituitary is capable of releasing growth hormone.For example, the compounds of Formula I or a pharmaceutically acceptablesalt or prodrug thereof can be administered in vivo to children andserum samples taken before and after such administration can be assayedfor growth hormone. Comparison of the amounts of growth hormone in eachof these samples would be a means for directly determining the abilityof the patient's pituitary to release growth hormone.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of Formula I or a pharmaceutically acceptablesalt or prodrug thereof in association with a pharmaceuticallyacceptable carrier. Optionally, the pharmaceutical compositions canfurther comprise an anabolic agent in addition to at least one of thecompounds of Formula I or a pharmaceutically acceptable salt or prodrugthereof, or another compound which exhibits a different activity, e.g.,an antibiotic or coccidiostat (e.g., monensin) growth promotant or anagent to treat osteoporosis or with other pharmaceutically activematerials wherein the combination enhances efficacy and minimizes sideeffects.

Growth promoting and anabolic agents include, but are not limited to,TRH, PTH, diethylstilbesterol, estrogens, β-agonists, theophylline,anabolic steroids, enkephalins, E series prostaglandins, compoundsdisclosed in U.S. Pat. No. 3,239,345, the disclosure of which is herebyincorporated by reference, e.g., zeranol; compounds disclosed in U.S.Pat. No. 4,036,979, the disclosure of which is hereby incorporated byreference, e.g., sulbenox; and peptides disclosed in U.S. Pat. No.4,411,890, the disclosure of which is hereby incorporated by reference.

The growth hormone secretagogues of this invention in combination withother growth hormone secretagogues such as the growth hormone releasingpeptides GHRP-6 and GHRP-1 as described in U.S. Pat. No. 4,411,890, thedisclosure of which is hereby incorporated by reference, andpublications WO 89/07110, WO 89/07111 and B-HT920 as well as hexarelinand the newly discovered GHRP-2 as described in WO 93/04081 or growthhormone releasing hormone (GHRH, also designated GRF) and its analogs orgrowth hormone and its analogs or somatomedins including IGF-1 and IGF-2or alpha-2-adrenergic agonists such as clonidine, xylazine, detomidineand medetomidine or serotonin 5HTID agonists such as sumitriptan oragents which inhibit somatostatin or its release such as physostigmineand pyridostigmine, are useful for increasing the endogenous levels ofGH in mammals. The combination of a GH secretagogue of this inventionwith GRF results in synergistic increases of endogenous growth hormone.

As is well known to those skilled in the art, the known and potentialuses of growth hormone are varied and multitudinous [See “Human GrowthHormone”, Strobel and Thomas, Pharmacological Reviews, 46, pg. 1-34(1994); T. Rosen et al., Horm Res, 1995; 43: pp. 93-99; M. Degerblad etal., European Journal of Endocrinology, 1995, 133: pp.180-188; J. O.Jorgensen, European Journal of Endocrinology, 1994, 130: pp. 224-228; K.C. Copeland et al., Journal of Clinical Endocrinology and Metabolism,Vol. 78 No. 5, pp. 1040-1047; J. A. Aloi et al., Journal of ClinicalEndocrinology and Metabolism, Vol. 79 No. 4, pp. 943-949; F. Cordido etal., Metab. Clin. Exp., (1995), 44(6), pp. 745-748; K. M. Fairhall etal., J. Endocrinol., (1995), 145(3), pp. 417-426; R. M. Frieboes et al.,Neuroendocrinology, (1995), 61(5), pp. 584-589; and M. Llovera et al.,Int. J. Cancer, (1995), 61(1), pp. 138-141]. Thus, the administration ofthe compounds of this invention for purposes of stimulating the releaseof endogenous growth hormone can have the same effects or uses as growthhormone itself. These varied uses of growth hormone may be summarized asfollows: stimulating growth hormone release in elderly humans orcompanion animals especially dogs, cats, camels and horses; treatinggrowth hormone deficient adult humans or other animals especially dogs,cats, camels and horses; preventing catabolic side effects ofglucocorticoids, treating osteoporosis, stimulating the immune system,accelerating wound healing, accelerating bone fracture repair, treatinggrowth retardation, treating congestive heart failure as disclosed inPCT publications WO 95/28173 and WO 95/28174 (an example of a method forassaying growth hormone secretagogues for efficacy in treatingcongestive heart failure is disclosed in R. Yang et al., Circulation,Vol. 92, No. 2, p.262, 1995), treating acute or chronic renal failure orinsufficiency; treating physiological short stature including growthhormone deficient children, treating short stature associated withchronic illness, treating obesity, treating growth retardationassociated with Prader-Willi syndrome and Turners syndrome; acceleratingthe recovery and reducing hospitalization of bum patients or followingmajor surgery such as gastrointestinal surgery; treating intrauterinegrowth retardation, skeletal dysplasia, hypercortisonism and Cushingssyndrome; replacing growth hormone in stressed patients; treatingosteochondrodysplasias, Noonans syndrome, sleep disorders, Alzheimer'sdisease, delayed wound healing, and psychosocial deprivation; treatingpulmonary dysfunction and ventilator dependency; attenuating proteincatabolic response after a major operation; treating malabsorptionsyndromes, reducing cachexia and protein loss due to chronic illnesssuch as cancer or AIDS; accelerating weight gain and protein accretionin patients on TPN (total parenteral nutrition); treatinghyperinsulinemia including nesidioblastosis; adjuvant treatment forovulation induction and to prevent and treat gastric and duodenalulcers; stimulating thymic development and preventing age-relateddecline of thymic function; adjunctive therapy for patients on chronichemodialysis; treating immunosuppressed patients and enhancing antibodyresponse following vaccination; improving muscle strength, increasingmuscle mass, mobility, maintenance of skin thickness, metabolichomeostasis, renal hemeostasis in the frail elderly; stimulatingosteoblasts, bone remodeling, and cartilage growth; treatingneurological diseases such as peripheral and drug induced neuropathy,Guillian-Barre Syndrome, amyotrophic lateral sclerosis, multiplesclerosis, cerebrovascular accidents and demyelinating diseases; andstimulating wool growth in sheep.

Uses of GH in farm animals raised for meat production such as chickens,turkeys, sheep, pigs and cattle include stimulation of pre- and post-natal growth, enhanced feed efficiency in animals raised for meatproduction, improved carcass quality (increased muscle to fat ratio)(Campbell, R. G. et al., (1989), J. Anim. Sci. 67, 1265; Dave, D. J.,Bane, D. P., (1990), The Compendium Food Anual, Vol. 12(1), 117; Holden,P. J., (1990), Agri-Practice, 11(3), 25; Claus, R., Weiber, U., (1994),Livestock Production Science, 37, 245; Roeder, R. et al., (1994), GrowthRegulation, 4, 101); increased milk production in dairy cattle (McBride,B. W. et al., (1988), Research and Development in Agriculture 5(1), 1;McDowell, G. H. et al., (1988), Aust. J. Biol. Sci., 41, 279); improvedbody composition; modification of other GH-dependent metabolic (Claus,R. and Weiber, U., (1994), Livestock Production Science, 37, 245) andimmunologic functions such as enhancing antibody response followingvaccination or improved developmental processes; and may have utility inaquaculture to accelerate growth and improve the protein-to-fat ratio infish.

Preferred uses in companion animals include stimulating endogenousgrowth hormone release in companion animals such as dogs, cats andhorses; treating disorders of aging (Detenbeck, L. C., Jowsey, J.,Clinical Orthopedics and Related Research, July-August 1969, No. 65, pp.76-80); stimulating thymic development and preventing age-relateddecline of thymic function (Goff, B. L. et al., Clinical andExperimental Immunology, 1987, 68:3, pp. 580-587; Morrison, W. B. etal., Am. J. Vet. Res., Jan. 1990, 51:1, pp. 65-70; Roth, J. A. et al.,Am. J. Vet. Res., 1984, Vol. 45, pp. 1151-1155); preventing age-relateddecline of thymic function; preventing age-related decline in cognition;accelerating wound healing (Jacks, T. et al., Vet. Surg. 1996, 25, (5),430); accelerating bone fracture repair (Pandey, S. K, Udupa, K. N.,Indian J. Vet. Surg. 1 (2): 73-78, July 1980); stimulating osteoblasts,bone remodelling and cartilage growth (Harris, W. H. et al., Calc. Tiss.Res., 10, 1972, pp. 1-13; Heaney, R. P. et al., Calc. Tiss. Res. 10,1972, pp. 14-22; Mankin. H. J. et al., J. of Bone and Joint Surgery,Vol. 60-A, #8, Dec. 1978, pp. 1071-1075); attenuating protein catabolicresponse after major surgery, accelerating recovery from bum injuriesand major surgeries such as gastrointestinal surgery; stimulating theimmune system and enhancing antibody response following vaccination;treating congestive heart failure, treating acute or chronic renalfailure or insufficiency, treating obesity; treating growth retardation,skeletal dysplasia and osteochondrodysplasias; preventing catabolic sideeffects of glucocorticoids; treating Cushing's syndrome; treatingmalabsorption syndromes, reducing cachexia and protein loss due tochronic illness such as cancer, accelerating weight gain and proteinaccretion in animals receiving total parenteral nutrition; providingadjuvant treatment for ovulation induction and to preventgastrointestinal ulcers; improving muscle mats, strength and mobility;maintenance of skin thickness, and improving vital organ function andmetabolic homeostasis.

The growth hormone secretagogues of this invention, compounds of FormulaI, or a pharmaceutically acceptable salt or prodrug thereof incombination with an alpha-2 adrenergic agonist are useful in promotingGH secretion in humans and other animals (See Cella, S. G. et al., ActaEndocrinologica (Copenh.) 1989, 121, pp. 177-184). As such, acombination of a compound of Formula I or a pharmaceutically acceptablesalt or prodrug thereof and an alpha-2 adrenergic agonist is useful inthe treatment or prevention of frailty associated with aging, congestiveheart failure and obesity which comprises administering to a human oranother animal, especially dogs, cats and horses, in need of suchtreatment a combination of an alpha-2 adrenergic agonist and a compoundof Formula I or a pharmaceutically acceptable salt or prodrug thereof,defined above. Preferred alpha-2 adrenergic agonists include clonidine,which is disclosed in U.S. Pat. No. 3,202,660 the disclosure of which ishereby incorporated by reference, xylazine, which is disclosed in U.S.Pat. No. 3,235,550 the disclosure of which is hereby incorporated byreference and medetomidine, which is disclosed in U.S. Pat. No.4,544,664 the disclosure of which is hereby incorporated by reference.In another aspect, this invention provides methods for accelerating bonefracture repair and wound healing, attenuating protein catabolicresponse after a major operation, and reducing cachexia and protein lossdue to chronic illness, which comprise administering to a human oranother animal, especially dogs, cats and horses in need of suchtreatment a combination of an alpha-2 adrenergic agonist such asclonidine, xylazine or medetomidine and a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof. It has been shownthat alpha-2 adrenergic agonists cause release of endogenous growthhormone in human and canine subjects (Cella et al., Life Sciences(1984), 34:447-454; Hampshire J, Altszuler N., American Journal ofVeterinary Research (1981), 42:6, 1073-1076; Valcavi et al., ClinicalEndocrinology (1988), 29:309-316; Morrison et al., American Journal ofVeterinary Research (1990), 51:1, 65-70;), and that theco-administration of an alpha-2 adrenergic agonist with growthhormone-releasing factor restores defective growth hormone secretion inaged dogs (Arce et al., Brain Research (1990), 537:359-362; Cella et.al., Neuroendocrinology (1993), 57:432-438).

This invention also relates to a method of treating insulin resistantconditions such as Non-insulin Dependent Diabetes Mellitus (NIDDM) andreduced glycemic control associated with obesity and aging in a mammalin need thereof which comprises administering to said mammal aneffective amount of a compound of the Formula I or a pharmaceuticallyacceptable salt or prodrug thereof.

This invention is directed to the use of growth hormone secretagoguesspecifically growth hormone releasing peptides (GHRP) or GHRP mimeticsof Formula I or a pharmaceutically acceptable salt or prodrug thereof toimprove glycemic control. Agents that increase growth hormone (GH)levels would not be expected to have this effect since it is widelyrecognized that GH is diabetogenic in animals and in humans. Inacromegalics, glucose utilization and suppression of hepatic glucoseproduction are impaired (see Hansen, I., et al., Am J Physiol, 250:E269(1986)). In this disease of GH excess, impaired glucose handling andhyperinsulinemia have been reversed by pituitary surgery or chemotherapywhich reduced GH levels (see Levin S. R., et al., Am J Med. 57:526(1974), Feek, C. M., et al., J Clin Endocrinol 22:532 (1981)).Furthermore, administration of GH to older subjects causedhyperglycemia, glucose intolerance and hyperinsulinemia in numerousstudies (see Aloia, J.F., et al., J Clin Endocrinol Metab, 43:992(1976); Binnerts et al., J Clin Endocrinol Metab, 67:1312 (1988);Marcus, R., et al., J Clin Endocrinol Metab, 70:519 (1990)). Therefore,GH therapy is contra-indicated for individuals with diabetes or those atrisk for diabetes.

It will be known to those skilled in the art that there are numerouscompounds now being used in an effort to treat the diseases ortherapeutic indications enumerated above. Combinations of thesetherapeutic agents, some of which have also been mentioned above, withgrowth promotant, exhibit anabolic and desirable properties of thesevarious therapeutic agents. In these combinations, the therapeuticagents and the growth hormone secretagogues of this invention may beindependently and sequentially administered in any order orco-administered in dose ranges from one one-hundredth to one times thedose levels which are effective when these compounds and secretagoguesare used singly. Combined therapy to inhibit bone resorption, preventosteoporosis, reduce skeletal fracture, enhance the healing of bonefractures, stimulate bone formation and increase bone mineral densitycan be effectuated by combinations of bisphosphonates and the growthhormone secretagogues of this invention. See PCT publication WO 95/11029for a discussion of combination therapy using bisphosphonates and GHsecretagogues. The use of bisphosphonates for these utilities has beenreviewed, for example, by Hamdy, N.A.T., Role of Bisphosphonates inMetabolic Bone Diseases, Trends in Endocrinol. Metab., 1993, 4, pages19-25. Bisphosphonates with these utilities include but are not limitedto alendronate, tiludronate, dimethyl-APD, risedronate, etidronate,YM-175, clodronate, pamidronate, and BM-210995 (ibandronate). Accordingto their potency, oral daily dosage levels of the bisphosphonate ofbetween 0.1 mg/kg and 5 g/kg of body weight and daily dosage levels ofthe growth hormone secretagogues of this invention of between 0.01 mg/kgto 20 mg/kg of body weight are administered to patients to obtaineffective treatment of osteoporosis.

The compounds of this invention may be combined with a mammalianestrogen agonist/antagonist. Any estrogen agonist/antagonist may be usedas the second compound of this invention. The term estrogenagonist/antagonist refers to compounds which bind with the estrogenreceptor, inhibit bone turnover and prevent bone loss. In particular,estrogen agonists are herein defined as chemical compounds capable ofbinding to the estrogen receptor sites in mammalian tissue, andmimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art according to standard assaysincluding estrogen receptor binding assays, standard bonehistomorphometric and densitometer methods (see Eriksen E.F. et al.,Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S.J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below,h however, other estrogenagonists/antagonists will be known to those skilled in the art. Apreferred estrogen agonist/antagonist is droloxifene: (phenol,3-[1-[4[2-(dimethylamino)ethoxy]-phenyl]-2-phenyl-1-butenyl]-, (E)-) andassociated compounds which are disclosed in U.S. Pat. No. 5,047,431, thedisclosure of which is hereby incorporated by reference.

Another preferred estrogen agonist/antagonist is tamoxifen:(ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl,(Z)-2,2-hydroxy-1,2,3-propanetricarboxylate (1:1)) and associatedcompounds which are disclosed in U.S. Pat. No. 4,536,516, the disclosureof which is hereby incorporated by reference. Another related compoundis 4-hydroxy tamoxifen which is disclosed in U.S. Pat. No. 4,623,660,the disclosure of which is hereby incorporated by reference.

Another preferred estrogen agonist/antagonist is raloxifene: (methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-hydrochloride)and associated compounds which are disclosed in U.S. Pat. No. 4,418,068,the disclosure of which is hereby incorporated by reference.

Another preferred estrogen agonist/antagonist is idoxifene: Pyrrolidine,1-[-[4-[[1-(4iodophenyl)-2-phenyl-1-Butenyl]phenoxy]ethyl] andassociated compounds which are disclosed in U.S. Pat. No. 4,839,155, thedisclosure of which is hereby incorporated by reference.

Other preferred estrogen agonist/antagonists include compounds asdescribed in commonly assigned U.S. Pat. No. 5,552,412 the disclosure ofwhich is hereby incorporated by reference. Especially preferredcompounds which are described therein are:

cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-hydroxy-1,2,3,4-tetrahydronaphthalene;

1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)hydroxy-1,2,3,4-tetrahydroisoquinoline;

cis-6-(4hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;and

1-(4′-pyrrolidinolethoxyphenyl)-2-phenylhydroxy-1,2,3,4-tetrahydroisoquinoline.

Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814, the disclosure of which is hereby incorporated by reference.U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

The following paragraphs provide preferred dosage ranges for variousanti-resorptive agents.

The amount of the anti-resorptive agent to be used is determined by itsactivity as a bone loss inhibiting agent. This activity is determined bymeans of an individual compound's pharmacokinetics and its minimalmaximal effective dose in inhibition of bone loss using a protocol suchas those referenced above.

In general an effective dosage for the activities of this invention, forexample the treatment of osteoporosis, for the estrogenagonists/antagonists (when used in combination with a compound ofFormula I or a pharmaceutically acceptable salt or prodrug thereof ofthis invention) is in the range of 0.01 to 200 mg/kg/day, preferably 0.5to 100 mg/kg/day.

In particular, an effective dosage for droloxifene is in the range of0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, an effective dosage for raloxifene is in the range of 0.1to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.

In particular, an effective dosage for tamoxifen is in the range of 0.1to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, an effective dosage for

cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)+hydroxy-1,2,3,4-tetrahydroisoquinoline;

cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or

1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineis in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10mg/kg/day.

In particular, an effective dosage for 4-hydroxy tamoxifen is in therange of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

Assay for Stimulation of GH Release from Rat Pituicytes

Compounds that have the ability to stimulate GH secretion from culturedrat pituitary cells are identified using the following protocol. Thistest is also useful for comparison to standards to determine dosagelevels. Cells are isolated from pituitaries of 6-week old male Wistarrats. Following decapitation, the anterior pituitary lobes are removedinto cold, sterile Hank's balanced salt solution without calcium ormagnesium (HBSS). Tissues are finely minced, then subjected to twocycles of mechanically assisted enzymatic dispersion using 10 U/mLbacterial protease (EC 3.4.24.4, Sigma P-6141, St. Louis, Mo.) in HBSS.The tissue-enzyme mixture is stirred in a spinner flask at 30 rpm in a5% CO₂ atmosphere at about 37° C. for about 30 min., with manualtrituration after about 15 min. and about 30 min. using a 10-mL pipet.This mixture is centrifuged at 200×g for about 5 min. Horse serum (35%final concentration) is added to the supernatant to neutralize excessprotease. The pellet is resuspended in fresh protease (10 U/mL), stirredfor about 30 min. more under the previous conditions, and manuallytriturated, ultimately through a 23-gauge needle. Again, horse serum(35% final concentration) is added, then the cells from both digests arecombined, pelleted (200×g for about 15 min.), resuspended in culturemedium (Dulbecco's Modified Eagle Medium (D-MEM) supplemented with 4.5g/L glucose, 10% horse serum, 2.5% fetal bovine serum, 1% non-essentialamino acids, 100 U/mL nystatin and 50 mg/mL gentamycin sulfate, Gibco,Grand Island, N.Y.) and counted. Cells are plated at 6.0-6.5×10⁴ cellsper cm² in 48-well Costar™ (Cambridge, Mass.) dishes and cultured for3-4 days in culture medium.

Just prior to GH secretion assay, culture wells are rinsed twice withrelease medium, then equilibrated for about 30 minutes in release medium(DMEM buffered with 25 mM Hepes, pH 7.4 and containing 0.5% bovine serumalbumin at 37° C.). Test compounds are dissolved in DMSO, then dilutedinto pre-warmed release medium. Assays are run in quadruplicate. Theassay is initiated by adding 0.5 mL of release medium (with vehicle ortest compound) to each culture well. Incubation is carried out at about37° C. for about 15 minutes, then terminated by removal of the releasemedium, which is centrifuged at 2000×g for about 15 minutes to removecellular material. Rat growth hormone concentrations in the supernatantsare determined by a standard radioimmunoassay protocol described below.

Measurement of Rat Growth Hormone

Rat growth hormone concentrations were determined by double antibodyradioimmunoassay using a rat growth hormone reference preparation(NIDDK-rGH-RP-2) and rat growth hormone antiserum raised in monkey(NIDDK-anti-rGH-5) obtained from Dr. A. Parlow (Harbor-UCLA MedicalCenter, Torrence, Calif.). Additional rat growth hormone (1.5 U/mg,#G2414, Scripps Labs, San Diego, Calif.) is iodinated to a specificactivity of approximately 30 μCi/μg by the chloramine T method for useas tracer. Immune complexes are obtained by adding goat antiserum tomonkey IgG (ICN/Cappel, Aurora, Ohio) plus polyethylene glycol, MW10,000-20,000 to a final concentration of 4.3%; recovery is accomplishedby centrifugation. This assay has a working range of 0.08-2.5 μg ratgrowth hormone per tube above basal levels.

Assay for Exogenously-Stimulated Growth Hormone Release in the Rat afterIntravenous Administration of Test Compounds

Twenty-one day old female Sprague-Dawley rats (Charles River Laboratory,Wilmington, Mass.) are allowed to acclimate to local vivarium conditions(24° C., 12 hr light, 12 hr dark cycle) for approximately 1 week beforecompound testing. All rats are allowed access to water and a pelletedcommercial diet (Agway Country Food, Syracuse N.Y.) ad libitum. Theexperiments are conducted in accordance with the NIH Guide for the Careand Use of Laboratory Animals.

On the day of the experiment, test compounds are dissolved in vehiclecontaining 1% ethanol, 1 mM acetic acid and 0.1% bovine serum albumin insaline. Each test is conducted in three rats. Rats are weighed andanesthetized via intraperitonèal injection of sodium pentobarbital(Nembutol®, 50 mg/kg body weight). Fourteen minutes after anestheticadministration, a blood sample is taken by nicking the tip of the tailand allowing the blood to drip into a microcentrifuge tube (baselineblood sample, approximately 100 μl). Fifteen minutes after anestheticadministration, test compound is delivered by intravenous injection intothe tail vein, with a total injection volume of 1 mL/kg body weight.Additional blood samples are taken from the tail at 5, 10 and 15 minutesafter compound administration. Blood samples are kept on ice until serumseparation by centrifugation (1430×g for 10 minutes at 10° C.). Serum isstored at −80° C. until serum growth hormone determination byradioimmunoassay as described above.

Assessment of Exogenously-Stimulated Growth Hormone Release in the Dogafter Oral Administration

On the day of dosing, the test compound is weighed out for theappropriate dose and dissolved in water. Doses are delivered at a volumeof 0.5-3 mL/kg by gavage to 2-4 dogs for each dosing regimen. Bloodsamples (5 mL) are collected from the jugular vein by direct venapuncture pre-dose and at 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 and 24hours post dose using 5 mL vacutainers containing lithium heparin. Theprepared plasma is stored at −20° C. until analysis.

Measurement of Canine Growth Hormone

Canine growth hormone concentrations are determined by a standardradioimmunoassay protocol using canine growth hormone (antigen foriodination and reference preparation AFP-1983B) and canine growthhormone antiserum raised in monkey (AFP-21452578) obtained from Dr. A.Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Tracer isproduced by chloramine T-iodination of canine growth hormone to aspecific activity of 20-40 μCi/μg. Immune complexes are obtained byadding goat antiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) pluspolyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%;recovery is accomplished by centrifugation. This assay has a workingrange of 0.08-2.5 μg canine GH/tube.

Assessment of Canine Growth Hormone and Insulin-Like Growth Factor-1Levels in the Dog after Chronic Oral Administration

The dogs receive test compound daily for either 7 or 14 days. Each dayof dosing, the test compound is weighed out for the appropriate dose anddissolved in water. Doses are delivered at a volume of 0.5-3 ml/kg bygavage to 5 dogs for each dosing regimen. Blood samples are collected atdays 0, 3, 7, 10 and 14. Blood samples (5 ml) are obtained by directvenipuncture of the jugular vein at pre-dose, 0.17, 0.33, 0.5, 0.754, 1,2, 3, 6, 8, 12 and 24 hours post administration on days 0, 7 and 14using 5 ml vacutainers containing lithium heparin. In addition, blood isdrawn pre-dose and 8 hours on days 3 and 10. The prepared plasma isstored at −20° C. until analysis.

Female Rat Study

This study evaluates the effect of chronic treatment with a GHRP mimeticon weight, body composition and non-fasting plasma concentrations ofglucose, insulin, lactate and lipids in estrogen-deficient andestrogen-replete female rats. Acute responsiveness of serum GH levels toi.v. administration of the GH releasing agent was assessed on the lastday of dosing. Body weight was monitored weekly throughout the treatmentperiod; additionally, body composition and plasma levels of glucose,insulin, lactate, cholesterol and triglycerides were assessed at the endof treatment.

Virgin female Sprague-Dawley rats were obtained from Charles RiverLaboratories (Wilmington, Mass.) and underwent bilateral ovariectomy(Ovx) or sham-surgery (Sham) at approximately 12 weeks of age. For shamsurgeries, ovaries were exteriorized and replaced into the abdominalcavity. Following surgery the rats were housed individually in 20 cm×32cm×20 cm cages under standard vivarium conditions (about 24° C. withabout 12 hours light/12 hours dark cycle). All rats were allowed freeaccess to water and a pelleted commercial diet (Agway ProLab 3000, AgwayCountry Food, Inc., Syracuse, N.Y.). The experiment was conducted inaccordance with NIH Guidelines for the Care and Use of LaboratoryAnimals.

Approximately seven months post-surgery, Sham and Ovx rats were weighedand randomly assigned to groups. Rats were dosed daily by oral gavagewith 1 mL of either vehicle (1% ethanol in distilled-deionized water),0.5 mg/kg or 5 mg/kg of a growth hormone releasing agent for 90 days.Rats were weighed at weekly intervals throughout the study. Twenty-fourhours after the last oral dose, the acute response of serum growthhormone (GH) to test agent was assessed by the following procedure. Ratswere anesthetized with sodium pentobarbital 50 mg/kg. Anesthetized ratswere weighed and a baseline blood sample (˜100 μl) was collected fromthe tail vein. Test agent (growth hormone releasing agent or vehicle)was then administered intravenously via the tail vein in 1 mL.Approximately ten minutes after injection, a second 100 μl blood samplewas collected from the tail. Blood was allowed to clot at about 4° C.,then centrifuged at 2000×g for about 10 minutes. Serum was stored atabout −70° C. Serum growth hormone concentrations were determined byradioimmunoassay as previously described. Following this procedure, eachanesthetized rat underwent whole body scanning by dual-energy X-rayabsorptiometry (DEXA, Hologic QDR 1000/W, Waltham Mass.). A final bloodsample was collected by cardiac puncture into heparinized tubes. Plasmawas separated by centrifugation and stored frozen as described above.

Plasma insulin is determined by radioimmunoassay using a kit from BinaxCorp. (Portland, Me.). The interassay coefficient of variation is ≦10%.Plasma triglycerides, total cholesterol, glucose and lactate levels aremeasured using Abbott VP™ and VP Super System® Autoanalyzer (AbbottLaboratories, Irving, Tex.), using the A-Gent™ Triglycerides,Cholesterol and Glucose Test reagent systems, and a lactate kit fromSigma, respectively. The plasma insulin, triglycerides, totalcholesterol and lactate lowering activity of a growth hormone releasingpeptide (GHRP) or GHRP mimetic such as a compound of Formula I, aredetermined by statistical analysis (unpaired t-test) with thevehicle-treated control group.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitonèal, intravenous or subcutaneousinjection, or implant) nasal, vaginal, rectal, sublingual, or topicalroutes of administration and can be formulated with pharmaceuticallyacceptable carriers to provide dosage forms appropriate for each routeof administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules and for companion animals the solid dosageforms include an admixture with food and chewable forms. In such soliddosage forms, the active compound is admixed with at least one inertpharmaceutically acceptable carrier such as sucrose, lactose, or starch.Such dosage forms can also comprise, as is normal practice, additionalsubstances other than such inert diluents, e.g., lubricating agents suchas magnesium stearate. In the case of capsules, tablets and pills, thedosage forms may also comprise buffering agents. Tablets and pills canadditionally be prepared with enteric coatings. In the case of chewableforms, the dosage form may comprise flavoring agents and perfumingagents.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. Generally, dosagelevels of between 0.0001 to 100 mg/kg of body weight daily areadministered to humans and other animals, e.g., mammals, to obtaineffective release of growth hormone.

A preferred dosage range in humans is 0.01 to 5.0 mg/kg of body weightdaily which can be administered as a single dose or divided intomultiple doses.

A preferred dosage range in animals other than humans is 0.01 to 10.0mg/kg of body weight daily which can be administered as a single dose ordivided into multiple doses. A more preferred dosage range in animalsother than humans is 0.1 to 5 mg/kg of body weight daily which can beadministered as a single dose or divided into multiple doses.

Throughout this disclosure the following abbreviations are used with thefollowing meanings:

BOC t-Butyloxycarbonyl

Bz Benzyl

BOP Benzotriazol-1-yloxy tris(dimethylamino) phosphoniumhexafluorophosphate

CBZ Benzyloxycarbonyl

CDl N,N′-Carbonyidiimidazole

DCC Dicyclohexylcarbodiimide

DEC 1,2-Diethylaminoethyl chloride hydrochloride

DMAP 4-Dimethylaminopyridine

DMF Dimethylformamide

DPPA Diphenylphosphoryl azide

EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc Ethyl acetate

Hex Hexane

HOAT 1-Hydroxy-7-azabenzotriazole

HOBT Hydroxybenzotnazole hydrate

HPLC High pressure liquid chromatography

Hz Hertz

KHMDS Potassium Bis(trimethylsilyl)amide

LHMDS Lithium Bis(trimethylsilyl)amide

MHz Megahertz

MS Mass Spectrum

NaHMDS Sodium Bis(trimethylsilyl)amide

NMR Nuclear Magnetic Resonance

PPAA 1-Propanephosphonic acid cyclic anhydride

PTH Parathyroid hormone

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TRH Thyrotropin releasing hormone

The preparation of the compounds of Formula I of the present inventioncan be carried out in sequential or convergent synthetic routes.Syntheses detailing the preparation of the compounds of Formula I in asequential manner are presented in the following reaction schemes.

Many protected amino acid derivatives are commercially available, wherethe protecting groups, Prt, Prt′ or Prt″, are, for example, BOC, CBZ,FMOC, benzyl or ethoxycarbonyl groups. Other protected amino acidderivatives can be prepared by literature methods well-known to oneskilled in the art. Some substituted piperazines and piperidines arecommercially available, and many other piperazines and 4-substitutedpiperidines are known in the literature. Various heterocyclicsubstituted piperidines and piperazines can be prepared followingliterature methods using derivatized heterocyclic intermediates.Alternatively, the heterocyclic rings of such compounds can bederivatized by standard means, such as coupling with CDl, hydrogenationof aromatic heterocycles, etc. as is well-known to those skilled in theart.

Many of the schemes illustrated below describe compounds which containprotecting groups Prt, Prt′ or Prt″, which can be any suitableprotecting group known to those skilled in the art. Benzyloxycarbonylgroups can be removed by a number of methods including, catalytichydrogenation with hydrogen in the presence of a palladium or platinumcatalyst in a protic solvent such as methanol. Preferred catalysts arepalladium hydroxide on carbon or palladium on carbon. Hydrogen pressuresfrom 1-1000 psi can be employed; pressures from 10 to 70 psi arepreferred. Alternatively, the benzyloxycarbonyl group can be removed bytransfer hydrogenation.

Removal of BOC protecting groups can be carried out using a strong acidsuch as trifluoroacetic acid or hydrochloric acid with or without thepresence of a cosolvent such as dichloromethane or methanol at atemperature of about −30° to 70° C., preferably about −5° to about 35°C.

Benzyl groups on amines can be removed by a number of methods includingcatalytic hydrogenation with hydrogen in the presence of a palladiumcatalyst in a protic solvent such as methanol. Hydrogen pressures from1-1000 psi can be employed; pressures from 10 to 70 psi are preferred.The addition and removal of these and other protecting groups arediscussed in detail by T. Greene in Protective Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981.

The variables shown in the following schemes are as described forcompounds of Formula I, above, unless otherwise indicated.

As illustrated in Scheme 1, coupling of a heterocyclic amine (HET at theNH) of formula 1-2, as defined for Formula I, with a protected aminoacid of formula 1-1, where Prt is a suitable protecting group, isconveniently carried out in an inert solvent such as dichloromethane orDMF by a coupling reagent such as EDC, DCC or DEC in the presence ofHOBT or HOAT. In the case where amine 1-2 is present as thehydrochloride salt, it is preferable to add one equivalent of a suitablebase such as triethylamine to the reaction mixture. Alternatively, thecoupling can be effected with a coupling reagent such as BOP in an inertsolvent such as methanol or with PPAA in a solvent like ethyl acetate.Such coupling reactions are generally conducted at temperatures of about−30° to about 80° C., preferably 0° to about 25° C. For a discussion ofother conditions used for coupling peptides see Houben-Weyl, Vol. XV,part II, E. Wunsch, Ed., George Theime Verlag, 1974, Stuttgart.Separation of unwanted side products and purification of intermediatesis achieved by chromatography on silica gel, employing flashchromatography (W. C. Still, M. Kahn and A. Mitra, J. Org. Chem. 43 29231978), by crystallization, or by trituration. Transformation of 1-3 intoan intermediate of formula 1-4 can be carried out by removal of theprotecting group Prt as described above.

As illustrated in Scheme 2, coupling of a heterocyclic amine of formula1-2, as defined in claim 1, with an amino acid of formula 2-1, where R⁷and R⁸ are not hydrogen, is conveniently carried out in a manner similarto that described in Scheme 1.

As illustrated in Scheme 3, an intermediate ether of formula 3-2 can beprepared by treating an amino acid of formula 3-1, where Prt is asuitable protecting group, with a base such as potassium carbonate orsodium hydride followed by an alkyl halide, benzyl halide, tosylate ormesylate such as benzylbromide in a suitable solvent such as DMF or THF.Deprotection of the amine transforms 3-2 into 3-3. Alternatively, manyamino acids of formula 3-3 are commercially available. R is a groupdefined for R³ in Formula I, above.

As illustrated in Scheme 4, intermediates of formula 4-2 can be preparedby treating an acid of formula 4-1 with hydroxysuccinimide in thepresence of a coupling agent such as EDC in an inert solvent such asmethylene chloride. Treating 4-2 with an amino acid of formula 4-3 in asolvent such as DMF in the presence of a base such asdiisopropylethylamine produces compounds of formula

As illustrated in Scheme 5, dipeptides of formula 2-1, where R⁷ and R⁸are not hydrogen, is conveniently synthesized by the proceduresdescribed in Scheme

Intermediate esters of formula 6-2, where Prt and Prt′ are protectinggroups, preferrably Prt′ is a carbamate protecting group such as CBZ,can be prepared by treating an acid of formula 6-1 with a base such aspotassium carbonate followed by an alkyl halide such as iodomethane in asuitable solvent such as DMF. Alternatively, an ester of formula 6-2 canbe prepared by reacting an acid of formula 6-1 with diazomethane. Forthe preparation of compound 6-2 see Bigge, C.F. et al., Tet. Lett.,1989, 30, 5193-5196. Intermediate 6-4 is generated by alkylating ester6-2 with a reagent such as an alkyl halide, tosylate or mesylate with abase such as NaHMDS in a suitable solvent system such as DMF/THF at atemperature of about −78° C.

Intermediate carbamates of formula 6-5 can be prepared by reacting anintermediate of formula 6-4 with a hydride such as sodium borohydride orsuperhydride. Transformation of intermediate 6-5 to 6-6 can be achievedby removal of the protecting group Prt as described above.

Transformation of intermediate 6-4 to 7-1 can be achieved by removal ofthe protecting group Prt′ as described above. Intermediate ureas offormula 7-5 can be prepared by reacting an intermediate of formula 7-1with either an acyl imidizolide of formula 7-2, an isocyanate of formula7-30 or phosgene (or other phosgene equivalent) followed by an amine offormula 7-4 in the presence of a suitable base such as triethylamine.When R¹ is —CH₂-pyridyl it is preferred to use an isocyanate or acylimidizolide. Transformation of 7-5 to 7-6 can be achieved by removal ofthe protecting group Prt as described above.

An intermediate benzylamine of formula 8-1 can be prepared by treatingan amine of formula 7-1 with a base such as diisopropylethylaminefollowed by a benzyl halide such as benzyl bromide in a suitable solventsuch as acetonitrile. Alternatively, 8-1 can be prepared by treating 7-1with benzaldehyde and a suitable reducing agent such as NaCNBH₃ orNa(OAc)₃BH in a suitable solvent such as methanol or dichloromethane. Analcohol of the formula 8-2 can be prepared by reducing an intermediateof the formula 8-1 with a reducing agent such as superhydride in asuitable solvent such as THF. An alcohol of the formula 8-2 can beoxidized to an aldehyde of the formula 8-3 with an oxidizing agent suchas oxalyl chloride/DMSO in a suitable solvent such as dichloromethane ata temperature of about −78° C., with the later addition of a base suchas triethylamine to neutralize the reaction mixture (Swem-type oxidabon,see Mancuso, A.J., Swem, D., Syhthesis, 1981, pp. 165-185). Compounds offormula 8-5 can be prepared by treating an aldehyde of formula 8-3 withan amine of formula 84 in the presence of a suitable reducing agentwhich include alkali metal borohydrides and cyanoborohydrides. Thepreferred reducing agent is sodium cyanoborohydride. Sodium borohydrideand sodium triacetoxyborohydride may also be used. For a general reviewof reductive aminations see R. F. Borch, Aldrichimica Acta, 8, 3-10(1975). Removal of the benzyl group to give 8-6 can be accomplished by anumber of reductive methods including hydrogenation in the presence ofplatinum or palladium catalyst in a protic solvent such as methanol.Cyclization of a diamine of formula 8-6 with CDl or other phosgeneequivalents generates a compound of formula 8-7. Removal of theprotecting group, as described above, transforms 8-7 into 8-8.

As illustrated in Scheme 9, an intermediate hydantoin of formula 9-4 canbe prepared in three steps. An ester of formula 9-1, prepared bycleavage of Prt′ from 6-2, can be acylated with an acyl imidizolide offormula 7-2, an isocyanate of formula 7-3, or phosgene (or otherphosgene equivalent) followed by an amine of formula 7-4 in the presenceof a suitable base such as triethylamine. Transformation of 9-3 to 9-4can be accomplished by removal of the protecting group Prt as describedabove.

Intermediates of formula 10-1 can be prepared by treating a compound offormula 7-1 with an acyl chloride or other activated carboxylic acidderivative and a suitable base, such as TEA orN,N-diisopropylethylamine. Cyclization of a compound of formula 10-1occurs upon treating 10-1 with a strong base such as LHMDS at a suitabletemperature, about −78° C. to 40° C., to produce an intermediate offormula 10-2. When R⁹ and/or R¹⁰ is H, 10-2 may be alkylated with areagent such as methyl iodide in the presence of a base like NaH to give10-2 where R⁹ and R¹⁰ are not H. Removal of the protecting group, asdescribed above, transforms 10-2 to 10-3.

Intermediate α,β-unsaturated esters of formula 11-3 (R is an alkylgroup) can be prepared by olefinating 11-1 with a reagent such as theanion generated upon treating trimethylphosphonoacetate with a strongbase such as potassium tert-butoxide in a suitable solvent such as THF.Catalytic hydrogenation, such as with Pd on carbon in the presence ofhydrogen, preferably at 1-4 atmospheres, in a suitable solvent, such asethyl acetate or methanol, reduces the double bond of 11-3 to produce11-4. Selective hydrolysis of the less hindered ester group in 11-4 canbe performed with a base such as an alkali metal hydroxide in anappropriate solvent, such as a mixture of water, methanol, and/ordioxane. A carboxylic acid of formula 11-5, thus produced can betransformed to 11-6 by converting 11-5 to an acyl azide, such as withDPPA and TEA in benzene, followed by rearrangement to an isocyanate byheating to reflux in a solvent such as benzene, which is then reactedwith benzyl alcohol to form 11-6. A lactam of formula 11-7 can beprepared by removal of the CBZ protecting group from the amine in 11-6,followed by cyclization of the amine with the adjacent ester group.Deprotection of this material provides 11-9, R²=H. Alternatively, amide11-7 can be alkylated by deprotonation with a strong base such as sodiumhydride, LHMDS, or KHMDS in a suitable solvent such as DMF or THFfollowed by treatment with an alkylating agent such as an alkyl halide,mesylate or tosylate. The product, 11-8, may then be deprotected, asdescribed above, to provide 11-9. One skilled in the art will recognizethat substitution next to the lactam nitrogen could have been introducedby alkylating ester 11-4 or by olefinating 11-1 to give atetra-substituted olefin analogous to 11-3.

Intermediate enol ethers of formula 12-1 can be prepared by treating11-1 (R is an alky( group) with a reagent, such as methoxymethyltriphenylphosphonium chloride and a strong base, such as potassiumtert-butoxide, in a suitable solvent such as THF. Hydrolysis of an enolether of formula 12-1 under acidic conditions produces aldehyde 12-2.Reduction of the aldehyde group to an alcohol, for example with sodiumborohydride in methanol, followed by cyclization converts 12-2 to alactone of formula 12-3. Deprotection of the nitrogen, as describedabove, affords 12-4. One skilled in the art will recognize that anR^(1A) substituent could have been introduced by alkylating aldehyde12-2. In addition, substitution next to the lactone oxygen (R⁹/R¹⁰)could be introduced by olefinating 11-1 to give a tetra-substitutedolefin and by treating the latter ketone or aldehyde (12-2) with analkyl metal such as a Grignard reagent.

Reduction of the ketone in 11-1 (R is an alkyl group) to an alcohol witha suitable reducing reagent, such as with sodium borohydride inmethanol, converts 11-1 to 13-1. Hydrolysis of the ester group in 13-1according to the method discussed in Scheme 11 produces acid 13-2.Transformation of 13-2 to 13-3 can be achieved by converting 13-2 toacyl azides, for instance with DPPA and TEA in a solvent such asbenzene, followed by rearrangement to isocyanates, which then reactintramolecularly with the adjacent alcohol to form carbamate 13-3.Deprotection of 13-3 as described above would provides 13-5 where R² isH. Alternatively, carbamate 13-3 can be alkylated by deprotonation witha strong base such as sodium hydride, LHMDS, or KHMDS in a suitablesolvent such as DMF or THF followed by treatment with an alkylatingagent such as an alkyl halide (R²-halide), mesylate or tosylate. Removalof the protecting group, as described above, transforms 13-4 to 13-5.One skilled in the art will recognize that an R^(1A) substituent couldhave been introduced by treating ketone 11-1 with an alkyl metalreagent, such as methyl magnesium bromide, at a suitable temperature fora Grignard reaction.

Removal of the carbamate protecting group, Prt, from 11-1 (R is an alkylgroup) produces 14-1. Reprotection, such as with a benzyl group gives14-2. Treating 14-2 with hydroxylamine yields an oxime of formula 14-3.The oxime and ester groups in 14-3 can be reduced to an amine andalcohol, respectively, to form 14-4 with a suitable reducing reagent,such as with LAH in THF. Transformation of 14-4 to a carbamate offormula 14-5 can be achieved by reaction of 14-4 with CDl or anotherphosgene equivalent in the presence of a base like TEA and solvent suchas DME. Deprotecton of 14-5 produces 14-7 where R² is H. Alternatively,alkylation of the carbamate as described above (Scheme 13) affords 14-6,which can be deprotected, as described above, to give 14-7.

Treating 15-1 with a strong base such as sodium hydride in a suitablesolvent such as DMF, followed by treatment with an alkylating agent,such as an alkyl halide, mesylate or tosylate, produces an N-substitutedimide of formula 15-2. Reduction of the pyridine ring by catalytichydrogenation, such as with Pd on carbon in an ethanolic HCl solutionconverts 15-2 to 15-3. Protection of the nitrogen, such as with a benzylgroup, gives 15-4. A compound of the formula 15-5 can be generated upondeprotonation of 154 with a suitable strong base such as LHMDS in asolvent such as THF at a temperature of about −78° C., followed byalkylation with an electrophile such as an alkyl halide such as benzylbromide. Cleavage of the protecting group, as described above, thengives 15-6.

Deprotection of 16-1 as described above produces 16-2.

Condensation of 17-1 (R is an alkyl group) with an amidine in a solventsuch as ethanol at an elevated temperature, preferably refluxingsolvent, produces a heterocyclic intermediate of formula 17-2.Deprotection of 17-2, as described above, gives an intermediate offormula 17-3.

An intermediate amine of formula 18-2 can be prepared from a ketone offormula 11-1 (R is an alkyl group) by reductive amination as describedabove (see Scheme 8). Protection of the secondary amine in 18-2 produces18-3. Intermediate carboxylic acids of formula 18-4 can be prepared byhydrolysis of the ester group of formula 18-3 (see Scheme 11).Transformation of 18-4 to 18-5 can be achieved through an intermediateacyl azide as described above (see Scheme 11). Cyclization of anintermediate of formula 18-5 at a suitable temperature after removingPrt′ yields an intermediate urea of formula 18-6. Deprotection of 18-6provides 18-8 where R^(2′)is H. Alternatively, urea 18-6 can bealkylated by deprotonation with a strong base such as sodium hydride,LHMDS, or KHMDS in a suitable solvent such as DMF or THF followed bytreatment with an alkylating agent such as an alkyl halide, mesylate ortosylate. Removal of the protecting group transforms 18-7 to 18-8 whereR² and R²′are each alkyl.

As illustrated in Scheme 19, reduction of a ketoester of formula 19-1,such as with sodium borohydride in methanol, preferably at 0° C.,produces an alcohol of formula 19-2. An intermediate of formula 19-3 canbe prepared by protection of the hydroxyl group in an intermediate offormula 19-2 with a suitable protecting group, such as forming atetrahydropyranyl acetal or silyl ether. Transformation of the ester offormula 19-3 to amide 19-5 can be achieved as described above (seeScheme 11). Deprotection of the hydroxy group of 19-5 yields the freealcohol intermediate, which can be oxidized to an intermediate ketone offormula 19 with a suitable oxidizing agent, such as pyridiniumchlorochromate or a Swern-type reagent (see Scheme 8). Transformation of19-6 to a cyclized carbamate of formula 19-7 can be achieved by treating19-6 with an alkyl metal, such as a Grignard reagent, in a suitablesolvent such as THF, followed by cyclization. Removal of the protectinggroup then yields 19-9 wherein R² is H. Alternatively, the carbamate of19-7 may be alkylated as described above (see Scheme 13) to afford 19-8,which can then be deprotected to provide 19-9. Those skilled in the artwill recognize that an R1A substituent could have been introduced byalkylating ketoester 19-1.

An alternate synthesis of lactam 11-7 is illustrated in Scheme 20. Analcohol of formula 13-1 can be, converted to an intermediate nitrile offormula 20-1 by first activating the hydroxyl of 13-1 (R is an alkylgroup), such as with methanesulfonyl chloride or methanesulfonic acid ina suitable solvent, such as methylene chloride in the presence of anamine base. Subsequent reaction of 20-1 (LO- is an activated hydroxyl)with a cyanide salt, such as potassium cyanide, then yields anintermediate nitrile of formula 20-2, which can be transformed to 11-7by catalytic hydrogenation of the nitrile to amine, which then reactswith the ester group to form lactam (11-7). Those skilled in the artwill recognize that an R^(1A) substituent could be introduced byalkylating nitrile 20-2.

Nitriles of formula 21-1 can be prepared from esters, acid halides andacids of formula 11-1 by a variety of known methods (for examples, seeR. Larock pages 976, 980 and 988 in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, VCHPublishers, 1989).

Homologation of ketones of formula 21-1 to provide 21-3 as describedabove (Scheme 12) yields an aldehyde of formula 21-3. Oxidation of thealdehyde group in 21-3, such as with sodium hypochlorite, provides anacid which can be esterified to give 21-4 by a number of methodsdescribed above (Scheme 6). Reduction of the nitrile group in a compoundof formula 21-4, such as by catalytic hydrogenation over Pd on carbon,gives an amine which will cyclize to give a lactam of formula 21-5.Deprotection of 21-5 yields 21-7, R² is H. Alternatively, alkylation ofthe amide of formula 21-5 as described above (Scheme 11) yields anN-substituted amide of formula 21-6, which can be deprotected to provide21-7. Those skilled in the art will recognize that an R^(1A) substituentcould have been introduced by alkylating ester 21-4.

Intermediate alcohols of formula 22-1 can be prepared by reducing theketone and ester groups of 11-1 (R is an alkyl group), such as with ametal borohydride or lithium aluminum hydride in a suitable solvent suchas THF. Selective protection of the primary hydroxyl group of theintermediate of formula 22-1 with a suitable protecting group, such as atrialkylsilyl ether or pivaloyl ester gives a secondary alcohol offormula 22-2. An intermediate nitrile of formula 22-4 can be preparedfrom the alcohol of formula 22-2 by methods described above (see Scheme20). An intermediate nitrile of formula 22-4 can be transformed to anester of formula 22-5 by alcoholysis of nitrile 22-4, for instance withaqueous HCl or sodium hydroxide in ethanol. Removal of the alcoholprotecting group and reaction of the hydroxyl group with the adjacentester group in 22-5 forms a lactone of formula 22-6. Deprotection asdescribed above yields 22-7. Those skilled in the art will recognizethat an R^(1A) substituent could have been introduced by treating ketone11-1 with the appropriate alkyl metal reagent. Substitution (R⁹, R¹⁰)adjacent to the lactone oxygen could then be introduced by treating theester with the appropriate alkyl metal reagent (the ketone would have tobe reduced if R^(1A) is not O).

Intermediate α,β-unsaturated nitriles of formula 23-1 can be prepared byolefinating 11-1 (R is an alkyl group) with a reagent such ascyanomethyltriphenylphosphonium chloride and a strong base, such asKHMDS, in a suitable solvent, such as THF. Reduction of the double bondin 23-1, such as with sodium borohydride in pyridine, produces nitrile23-2. The ester group of formula 23-2 can then be transformed to acarbamate of formula 23-4 by methods described above (see Scheme 11).Alcoholysis of the nitrile of 23-4 in an alcoholic solvent under acidiccondition produces an ester of formula 23-5. A lactam of formula 23-6can be prepared by removal of the CBZ protecting group, followed bycyclization of the amine with the adjacent ester group. Deprotection atthis stage provides 23-8, R² is H. Alternatively, alkylation of theamide (according to Scheme 11) provides an N-subsitituted lactam, whichcan be converted to 23-8 by deprotection as described above. One skilledin the art will recognize that an R^(1A) substituent could have beenintroduced by conjugate addition to the unsaturated nitrile (23-1), suchas with an alkyl cuprate. In addition, R⁹, R¹⁰ substituents can beintroduced next to the lactam carbonyl by alkylating nitrile 23-2.

As illustrated in Scheme 24, an alcohol of formula 24-1 can be preparedfrom 19-3 (R is an alkyl group) by reduction of the ester with areducing reagent such as lithium borohydride in a solvent such as THF. Anitrile of formula 24-2 can be prepared from the alcohols of formula24-1 by methods described above (see Scheme 20). Deprotection of thealcohol of 24-2 followed by oxidation of the hydroxyl as previouslydescribed (see Scheme 19) produces a ketone 24-3. Treating 24-3 with analkyl metal such as a Grignard reagent in a suitable solvent such as THFgives an intermediate of formula 24-4. The cyano group of 24-4 can thenbe converted to an ester by alcoholysis as described above (Scheme 22).Reaction of the tertiary alcohol with the neighboring ester forms alactone which can then be deprotected to give 24-5. One skilled in theart will recognize that an R^(1A)substituent could be introduced byalkylating ester 19-3. In addition, R⁹, R¹⁰ substituents could beintroduced adjacent to the lactone carbonyl by alkylation before finaldeprotection.

Intermediate of formula 25-1 (LO- is an activated hydroxyl) can beprepared by selective activation of the primary hydroxyl, for instanceby tosylation of the less hindered hydroxyl group of 20-1 with tosylchloride in a suitable solvent Treating 25-1 with a reagent such aspotassium cyanide in a suitable solvent produces a nitrile of formula25-2. Oxidation of the alcohol (see Scheme 19) of formula 25-2 gives aketone of formula 25-3. Transformation of 25-3 to 25-4 can be achievedby reductive amination as was described above (see Scheme 8). The cyanoamine of formula 25-4 can be converted to a lactam of formula 25-5 bytreating 25-4 with a strong acid or base in a protic solvent such asethanol. Removal of the protecting group on the secondary nitrogen canthen provide lactam 25-6. One skilled in the art rill recognize that R⁹,R¹⁰ substituents could be introduced by alkylation of lactam 25-5.

A lactone of formula 26-1 can be prepared by treating a cyano alcohol offormula 25-2 with a strong acid such as HCl, or a strong base such asNaOH, in a protic solvent such as EtOH. Deprotection, as describedabove, of the secondary amine of formula 26-1 gives 26-2. One skilled inthe art will recognize that R⁹, R¹⁰ substituents can be introduced byalkylation of lactone 26-1.

Intermediates of formula 27-1 can be prepared by reducing a lactam offormula 11-7 to a pyrrolidine with a suitable reducing reagent such asborane or lithium aluminum hydride in a suitable solvent such as THF.Treating 27-1 with an acyl chloride of formula RCOCI (where R is analkyl group) in a suitable solvent produces an intermediate amide offormula 27-2. Removal of the protecting group of the amide of formula27-2 by the method described previously gives an amide of formula 27-3.

A sulfonamide of formula 27-5 can be prepared by treating 27-1 with asulfonate such as tosyl chloride in the presence of a base such aspyridine to yield 27-4, followed by removal of the protecting group aspreviously described.

Intermediate diols of formula 28-1 (R is an alkyl group) can be preparedby treating 12-2 with a suitable reducing agent, such as lithiumborohydride, in an appropriate solvent, such as THF. Methods forconverting diol 28-1 to furan 28-2 include dehydration under acidicconditions, dehydration with a reagent such as Ph₃P(OEt)₂, or reactionwith a reagent such as toluenesulfonylchloride in the presence of a basefollowed by displacement of the activated alcohol with the remaininghydroxyl group. Removal of the protecting group from 28-2 subsequentlyforms a compound of formula 28-3. One skilled in the art will recognizethat an R^(1A) substituent can be added by alkylating aldehyde 12-2. Inaddition, R⁹, R¹⁰ substituents can be introduced by treating 12-2 withan alkyl metal reagent.

Intermediate aldehydes of formula 29-1 can be prepared by protecting thesecondary alcohol of 13-1 such as with a silyl ether, followed byreduction of the ester with a reducing reagent such asdiisobutylaluminum hydride at −78° C. in a suitable solventAlternatively, 13-1 can be reduced to the primary alcohol with a reagentsuch as lithium borohydride, and then oxidized to the aldehyde with avariety of reagents described above (see Scheme 8). Homologation ofaldehydes of formula 29-1 to saturated esters of formula 29-3 can beperformed as previously described (see similar homologation of ketonesin Scheme 11). Deprotection of the secondary alcohol of 29-3, followedby cyclization produces lactones of formula 29-4. Deprotection of 294will then give 29-5. An R⁹ substituent β to the lactone carbonyl may beintroduced by conjugate addition to unsaturated ester 29-2, such as withan alkyl cuprate. In addition, R⁹, R¹⁰ substituents could be introducednext to the lactone carbonyl by alkylating lactone 294.

Intermediate ketones of formula 30-1 can be prepared by deprotecting thesecondary hydroxyl of 29-3 (R is an alkyl group), followed by oxidationof the alcohol to a ketone (see Scheme 19). Reductive amination of 30-1with a primary amine as previously described (see Scheme 8) producesintermediate 30-3. Cyclization of 30-3 at a suitable temperature yieldsa lactam of formula 304, which can be deprotected to give 30-5. Oneskilled in the art will recognize that R⁹, R¹⁰ substituents can beintroduced by alkylation of lactam 304.

Homologation of 19-3 (R is an alkyl group) to an ester of formula 31-3can be performed analogously to routes described above (see Scheme 29).Removal of Prt′ of 31-3 gives a secondary alcohol which can be oxidizedas was previously described (see Scheme 19) to produce a ketone offormula 31-4. Treating 31-4 with an alkyl metal reagent, such as aGrignard reagent, in a suitable solvent produces intermediate 31-5,which can be cyclized to form lactone 316. Removal of the protectinggroup then produces 31-7. One skilled in the art will recognize that anR^(1A) substituent may be introduced by alkylation of ester 19-3. Asubstituent β to the lactone carbonyl may be introduced by conjugateaddition to unsaturated ester 31-2, such as with an alkyl cuprate. Also,R⁹, R¹⁰ substituents can be introduced next to the lactone by alkylationof 316.

Intermediate diols of formula 32-1 can be prepared by reducing thelactone group of 26-2 with a reagent such as lithium aluminum hydride ina suitable solvent such as THF at a suitable temperature. Selectiveprotection at the less hindered hydroxy group of 32-1, such as witht-butyldimethylsilyl chloride using triethylamine in the presence ofDMAP in a solvent such as dichloromethane, produces alcohol 32-2.Conversion of alcohol 32-2 to a nitrile of formula 324 may beaccomplished as described above (LO— is an activated hydroxyl group)(see Scheme 20). Alcoholysis of the cyano group of formula 32-4 (seeScheme 22), deprotection of the alcohol, and subsequent lactonizationforms lactones of formula 32-5. Deprotection of an amine of formula 32-5gives a lactone of formula 326. One skilled in the art will recognizethat R⁹, R¹⁰ substituents can be introduced β- to the ring oxygen inlactone 32-6 by alkylating lactone 26-2. Substitution a to the lactonering oxygen may be introduced by treating 26-2 with an alkyl metalreagent.

Intermediate nitriles of formula 33-2 can be prepared by homologating12-2 (R is an alkyl group), analogous to the ketone homologationdescribed in Scheme 23. Conversion of ester 33-2 to carbamates offormula 33-4 can be accomplished as described above (see Scheme 11).Alcoholysis of the cyano group of 33-4 as described above (see Scheme22) and removal of the CBZ protecting group, followed by cyclization ofthe amine with the adjacent ester group produces a lactam of formula33-5. Deprotection of 33-5 gives the lactam of formula 33-6.

Alternatively, alkylation of 33-5 in the usual fashion (see Scheme 11)gives 33-7, which can be deprotected to give 33-8. One skilled in theart will recognize that an R^(1A) substituent may be introduced byalkylating aldehyde 12-2. An R⁹ substituent may be introduced byconjugate addition to the unsaturated nitrile (33-1). R⁹, R¹⁰substitution can be introduced next to the lactam by alkylation of 33-7.

The homologation of 25-3 to give a lactam of formula 34-5 can beanalogously performed according to the procedures described in Scheme21. One skilled in the art will recognize that an R^(1A) substituent maybe introduced by alkylating 34-4 (R is an alkyl group). R⁹, R¹⁰substitution may be introduced by alkylating nitrile 341.

As illustrated in Scheme 35, catalytic hydrogenation of a nitrile offormula 23-2 (R is an alkyl group) gives an amine, followed bycyclization of the amine with the adjacent ester group to give lactamsof formula 35-1. Deprotection of 35-1 gives 35-3, R² is H.Alternatively, alkylation of lactam 35-1 as described above (see Scheme11) provides N-substituted amides of formula 35-2. Deprotection of 35-2affords 35-3. One skilled in the art will recognize that an R^(1A)substituent may be introduced by conjugate, addition to the unsaturatednitrile.

As illustrated in Scheme 36, selective reduction of the carboxylic acidgroup of 11-5 to an alcohol, such as by treating 11-5 (R is an alkylgroup) with borane in a suitable solvent, followed by cyclization of thealcohol and ester produces a lactone of the formula 36-1. Deprotectionof 36-1 then gives 36-2.

Intermediate alcohols of formula 37-1 can be prepared by reducing theketone of 21-1, such as with sodium borohydride in a solvent such asmethanol at a temperature of about 0° C. Reduction of the cyano group toan amine, such as by catalytic hydrogenation, affords aminoalcohol 37-2.Treating 37-2 with a reagent like CDl or other phosgene equivilent inthe presence of a base like TEA (see Scheme 14) produces a cyclizedcarbamate of formula 37-3. Deprotection of 37-3 then gives 37-5, R² isH. Alternatively, 37-3 may be alkylated as described above (see Scheme13) to give an N-substituted carbamate of formula 374, which isdeprotected to give 37-5. One skilled in the art will recognize that anR^(1A) substituent may be introduced by addition to ketone 21-1.

Intermediate aminoalcohols of formula 38-1 can be prepared by reducingan ester of formula 18-2 (R is an alkyl group), such as with lithiumborohydride. Treating 38-1 with a phosgene equivalent as described inScheme 14 produces a cyclized carbamate of formula 38-2. Deprotectionsubsequently provides 38-3.

Intermediate imines of formula 39-1 can be prepared by condensing theketone of 21-1 with a primary amine under dehydrating conditions, suchas azeotropic distillation using a solvent like benzene. Catalytichydrogenation to reduce the nitrile and imine converts 39-1 to 39-2.Treating 39-2 with a reagent like CDl, phosgene, or triphosgene in thepresence of a base like TEA produces the cyclized and N-substitutedureas of formula 39-3. Deprotection of this material provides 39-5 wherethe R² attached to the (2)-nitrogen is H. Alkylation of 39-3, such aswith sodium hydride and an alkyl halide produces the N,N′-substitutedureas of formula 39-4, which can be deprotected to provide 39-5 wherethe R² attached to the (2)-nitrogen is an alkyl group.

As illustrated in Scheme 40, ester 20-2 (R is an alkyl group) can beconverted to carbamate 40-2 as described above (see Scheme 11).Catalytic hydrogenation of 40-2 will reduce the nitrile and cleave theCBZ group to provide a diamine of formula 40-3. Acylating 40-3 with areagent such as CDl, phosgene, or triphosgene in the presence of a baselike TEA produces the cyclized ureas of formula 40-4. Deprotection atthis stage provides 40-6 where each R² is H. Alternatively, alkylationof 40-4, such as by deprotonation with a strong base like sodium hydridefollowed by reaction with an alkylating reagent like an alkyl halide,tosylate or mesylate produces the N,N′-substituted ureas of formula40-5. Deprotection then provides 40-6 where each R² is alkyl. Oneskilled in the art will recognize that an R^(1A) substituent may beintroduced by alkylation of nitrile 20-2.

Intermediate esters of formula 41-1 (R is an alkyl group) can beprepared by alcoholysis of the cyano group in 40-2 with ethanolic HCl.Reducing the ester group in 41-1, such as with lithium borohydride inTHF produces an alcohol of formula 41-2. Catalytic hydrogenation toremove the CBZ group to yield an amine as previously described converts41-2 to 41-3. Treating 41-3 with a reagent like CDl or other phosgeneequivalent in the presence of a base like TEA produces a carbamate offormula 41-4. Deprotection at this stage provides 416 where R² is H.Alternatively, transformation of 41-4 to N-substituted carbamates offormula 41-5 can be achieved by deprotonating 41-4 with a stong basesuch as sodium hydride in a solvent like DMF, followed by alkylationwith a reagent such as an alkyl halide, tosylate or mesylate.Deprotection then converts 41-5 to 416 where R² is alkyl.

Reaction of a ketoester of formula 42-1 with a chiral amine such asalpha-methylbenzylamine with a suitable aldehyde such as formaldehyde,or reaction of a vinyl ketoester of formula 42-2 with a chiral aminesuch as alpha-methylbenzylamine with a suitable aldehyde such asformaldehyde, affords a compound of formula 42-3 via a double Mannichreaction. Compound 42-3 is equivalent to 11-1 where d and e are 1, andmay be deprotected with a suitable catalyst such as palladium in thepresence of hydrogen to give 42-4. In addition, 42-3 could be isolatedas a single diastereomer (by selective cyclization or separation ofdiastereomers), thereby providing 424 as a single enantiomer.

Treatment of a compound of formula 43-1 with a base such as sodiumhydride in a solvent such as DMF followed by treatment withdiethylcarbonate generates the ethyl ester of compound 43-2 (R is analkyl group). Deprotection of the amine transforms 43-2 into 43-3. Itwill be recognized by one skilled in the art that 191 is equivalent to43-3.

Treatment of a malonic ester of formula 44-1 (R is an alkyl group) witha base such as sodium hydride in a solvent such as DMF and subsequenthydrogenolysis of the benzyl group with hydrogen and a catalyst such aspalladium in a suitable solvent such as methanol produces the ester offormula 43-2. Deprotection of the amine generates compounds of formula43-3. It will be recognized by one skilled in the art that 19-1 isequivalent to 43-3.

Treatment of a ketone of formula 45-1 with a secondary amine such aspiperidine in a suitable solvent such as benzene with removal of wateraffords an enamine of formula 45-2 (each R is an alkyl group).Alkylation of the enamine with an alpha-haloester such asethylbromoacetate in a suitable solvent such as benzene or THF using asuitable base such as LDA or NaN(SiMe₃)₂ affords a ketoester of formula45-3. Reduction with a mild reducing agent such as sodium borohydride inmethanol and subsequent cyclization then affords 26-1.

Treatment of a ketoester of formula 43-3 (R is an alkyl group) with aniodonium salt such as diphenyliodonium trifluoroacetate in a suitablesolvent such as t-butanol generates a ketoester of formula 11-1 where R¹is phenyl. See Synthesis, (9), 1984 p. 709 for a detailed description.

Treatment of a ketoester of formula 43-3 with an olefin such asacrylonitrile or nitroethylene generates a ketoester of formula 11-1where R¹ is CH₂CH₂CN or R¹ is CH₂CH₂NO₂.

Treatment of an ester of formula 43-3 (R is an alkyl group) with a basesuch as sodium hydride in a solvent such as DMF followed by an alkylhalide 48-1 generates a compound of formula 11-1 as illustrated inScheme 48.

Treatment of a ketoester of formula 43-2 with allyl bromide and asuitable base such as sodium hydride in a suitable solvent such as DMFaffords a ketoester of formula 49-1 (11-1, R² is allyl). Compound 49-1may then be converted to 13-4 as described in Scheme 13. Ozonolysis of13-4 in a suitable solvent such as methylene chloride followed bytreatment with a reducing agent such as dimethylsulfide affords analdehyde of formula 49-2. Oxidation of 49-2 affords a carboxylic acid offormula 49-3. Curtius rearrangement of 49-3, followed by hydrolysis ofthe intermediate isocyanate affords a primary amine of formula 49-4.Treatment of a compound of formula 49-4 with an isocyanate or carbamateaffords a urea of formula 49-5. Deprotection of the nitrogen affordscompounds of formula. 496 (13-5, R¹ is CH₂NHCONX⁶X⁶). Those skilled inthe art will recognize that other heterocycles, prepared in previousschemes, could be transformed analogously to the conversion of 13-4 to49-6.

Treatment of a compound of formula 49-2 with a primary amine of formulaHNX⁶ affords an imine of formula 50-1. Reduction of a compound offormula 50-1 affords a compound of formula 50-2. Treatment of a compoundof formula 50-2 with an acylating agent affords a compound of formula50-3. Deprotection of the nitrogen affords compounds of formula 50-4(13-5, R¹ is CH₂CH₂NX⁶COX⁶). Those skilled in the art will recognizethat other heterocycles, prepared in previous schemes, could betransformed in a manner analogous to the conversion of 49-2 to 50-4.

Treatment of a compound of formula 49-2 with a reducing agent such assodium borohydride affords a compound of formula 51-1. Reaction of 51-1with an acylating agent such as an isocyanate or carbamate affordscompounds of formula 51-2. Deprotection of the nitrogen affordscompounds of formula 51-3. Those skilled in the art will, recognize thatother heterocycles, prepared in previous schemes, could be transformedin a manner analogous to the conversion of 49-2 to 51-3.

Treatment of a compound of formula 51-1 with a phosphine such astriphenyl phosphine and an azo compound such as diethylazodicarboxylateand an oxindole affords a compound of formula 52-1. Deprotection of thenitrogen affords the compound of formula 52-3. Those skilled in the artwill recognize that other heterocycles, prepared in previous schemes,could be transformed in a manner analogous to the conversion of 49-2 to52-3.

Treatment of a ketoester of formula 43-3 with a chiral diol and addcatalyst with removal of water in a suitable solvent such as benzeneaffords a chiral ketal like formula 53-1. Alkylation of 53-1 with analkyl halide in the presence of a base such as LDA followed byacid-catalyzed hydrolysis of the ketal affords chiral ketoesters offormula 53-2. Ketoester 53-2 is a single enantiomer of 11-1 and mayhomologated in a similar fashion to give various heterocycles.

Treatment of a ketoester of formula 43-3 with a chiral amino acid estersuch as valine t-butyl ester affords a chiral enamine of formula 54-1.Alkylation of 54-1 with an alkyl halide in the presence of a base suchas LDA followed by acid-catalyzed hydrolysis of the enamine affordschiral ketoesters of formula 53-2.

Salt formation of 7-6 with a chiral acid affords a mixture ofdiastereomeric salts of formula 55-1. Crystallization of thediastereomeric salts affords the acid salt of chiral compounds offormula 55-2. Decomposition of the salt 55-2 with base liberates chiralcompounds of formula 55-3. This resolution scheme could be applied tothe resolution of other HET-bicyclic compounds described above.

As illustrated in Scheme 56, treatment of 6-4 (P¹ is CO₂Bn) with analkyl metal reagent like methyl magnesium bromide affords 56-1.Deprotection as usual then affords 56-2.

Compounds of formula 57-3 can be prepared from known phthalic orhomophthalic anhydrides by methods previously described by Welch,Willard M. (J.Org.Chem 47; 5; 1982; 886-888. J.Org.Chem.; 47; 5; 1982;886-888) or Machida, Minoru et al. (Heterocycles; 14; 9; 1980;1255-1258). Alternatively, the analogous phthalimides orhomophthalimides of formula 57-1 can be treated with the appropriatehydride reagent (e.g., NaBH₄) or organometallic reagent (e.g., methylGrignard), followed by treatment with sodium or potassium cyanide toproduce an intermediate of the formula 57-2. Compounds of formula 57-2can be converted to compounds of formula 57-3 as previously described byWelch, Willard M. (J.Org.Chem 47; 5; 1982; 886-888).

As illustrated in Scheme 58, intermediates of formula 58-4 can beprepared in four steps from compounds of formula 7-1. Compounds offormula 7-1 are treated with a suitable reducing agent such as SuperHydride® in a suitable solvent, preferably THF at a temperature of −20to 50° C., preferably at around 25° C. to give compounds of formula58-1. Amino alcohols of formula 58-1 are then treated with at least twoequivalents of methanesulfonyl chloride and at least two equivalents ofa suitable base, preferably pyridine in a suitable solvent, preferablypyridine at a temperature of −20 to 50° C. preferably around 25° C. togive intermediates of formula 58-2. Treatment of 58-2 with a strongbase, preferably sec-butyllithium at a temperature of around −78° C.followed by warming to a temperature of around 25° C. affordsintermediates of formula 58-3. Removal of the protecting group asdescribed above, transforms 58-3 into 58-4.

An alternative synthesis of lactam 11-8 is illustrated in Scheme 59. Analdehyde of formula 12-2 can be employed in a reductive amination withan amine and reducing agent, for example sodium triacetoxyborohydride.Subsequent cyclization of the amine with the adjacent ester groupaffords 11-8. One skilled in the art will recognize that an R^(1A)substituent could have been introduced adjacent to the aldehyde byalkylating aldehyde 12-2 according to well known procedures.

Aldehydes of formula 60-1 can be prepared by reducing 7-1 with an agentlike diisobutylaluminum hydride at a suitable temperature, preferably−78° C. to 0° C. in a suitable solvent, such as THF, methylene chloride,toluene or ether. This aldehyde may then be converted to amines of theformula 60-2 by the methods described in Scheme 8 to convert 8-3 to 8-5.In addition, an oxime may be formed by treating the aldehyde withhydroxylamine hydrochloride. Reduction of this oxime, such as withRaney-nickel provides 60-2 where R² is hydrogen. Treatment of thismaterial with phosgene, triphosgene, carbonyl diimidazole, or otherequivalent in the presence of a base, preferably a tertiary amine base,provides a route to ureas of formula 8-7. Those skilled in the art willrecognize that R² may have been a group, such as a benzyl or allylgroup, which could be cleaved to give 8-7 where R² is hydrogen.

Alternatively, compounds of the formula 8-7 may be prepared by reducingcarbamate protected ester 60-3, for example when R¹=CH₂-2-Pyr, accordingto well known reduction techniques to afford aldehyde 60-4 which maythen be converted to an amine, as described above, which is then reactedwith the carbamate at a suitable temperature to provide 8-7.

Olefin 61-1 may be prepared by olefinating aldehyde 60-1 with a reagentsuch as the anion generated upon treating a trialkylphosphono acetatewith an appropriate base, such as NaHMDS in a suitable solvent, such asTHF. Reduction of the olefin, by methods such as catalytic hydrogenation(see Scheme 11) or conjugate reduction with an agent such as the alkalimetal salt of a trialkylborohydride, such as lithiumtri-sec-butylborohydride, provides the compounds of formula 61-2. Thismaterial is cyclized at elevated temperatures in a reaction inertsolvent using cyclization conditions well known to those skilled in theart. Those skilled in the art will recognize that the cyclizationreaction may require the addition of a base such as potassium carbonate.Generally the reaction is carried out at reflux in a solvent such asmethanol. Deprotection of 61-3 affords compounds of formula 61-5 whereR⁹ and R¹⁰=H. Those skilled in the art will recognize that 61-3 can bealkylated under a variety of conditions, such as by treating 61-3 with astrong base, e.g., lithium diisopropylamide or LHMDS in a reaction inertsolvent such as THF at a suitable temperature, preferably −78° C. Theanion generated is treated with alkylating reagents such as alkylhalides or alkyl tosylates, such as methyl iodide, to give 61-4. Thisprocess may be repeated to introduce a second substituent. Deprotectionaffords compounds of formula 61-5. Those skilled in the art willrecognize that a R⁹ substituent can be introduced β to the lactam byconjugate addition to 61-1, such as would be afforded by the use of analkyl cuprate reagent.

An alternate synthesis of 61-3 is shown above. Reduction of ketoamide62-1, which is equivalent to 10-2 where R⁹ and R¹⁰ are hydrogen, with areducing agent such sodium borohydride, in an reaction inert solventsuch as methanol at a suitable temperature such as 0° C. affords alcohol62-2. The alcohol is reacted under standard elimination conditions wellknown to those skilled in the art to provide unsaturated lactam 61-3.Suitable elimination conditions include activating the alcohol, such asby converting it to the corresponding tosylate or mesylate, and thentreating the activated alcohol with base at a suitable temperature, forinstance with 1,8-diazabicyclo[5.4.0]undec-7-ene in refluxing toluene,or by deprotonating the amide with a strong base such as LHMDS. Thealcohol may also be eliminated at suitable temperatures in the presenceof a strong base or strong acid. Those skilled in the art will recognizethat these conditions may also cleave the protecting group (P).Reduction of 62-3, by methods such as catalytic hydrogenation (seeScheme 11) or conjugate reduction with an agent such as the alkali metalsalt of a trialklyborohydride, like lithium tri-sec-butylborohydride,will then provide 61-3. Those skilled in the art will recognize that aR⁹ substituent could have been introduced β to the lactam by conjugateaddition of a reagent, such as a cuprate, to the unsaturated lactam.

Compounds of formula 63-1 are prepared by deprotonating the alcohol witha strong base such as sodium hydride, LHMDS, KHMS or NaHMDS in asuitable solvent such as DMF or THF followed by treatment with analkylating agent such as an alkyl halide, mesylate or tosylate, forinstance, methyl iodide. The product is then deprotected according tomethods well known to those skilled in the art to provide 63-2.

General Experimental Procedures

Silica gel was used for column chromatography. Melting points were takenon a Buchi 510 apparatus and are uncorrected. Proton and carbon NMRspectra were recorded on a Varian XL-300, UNITYPlus-400, Bruker AC-300,or Bruker AC-250 at 25° C. Chemical shifts are expressed in parts permillion downfield from trimethylsilane. Particle beam mass spectra(PBMS) were obtained on a Hewlett-Packard 5989A spectrometer usingammonia as the source of chemical ionization. The protonated parent ionis reported as (M+1)⁺. For initial sample dissolution chloroform ormethanol was employed. Atmospheric Pressure Chemical Ionization massspectra (APcl MS) were obtained on a Platform II by Fisons (now calledMicromass Inc.) instrument. They are either run via +APcl (basic method)or +APcl (acid method). The mobile phase is 50:50H₂O:acetonitrile.Either a protonated parent (+APcl) or deprotonated parent ion (−APcl) isobserved (reported as (M+1)⁺ or (M−1)⁻). For initial sample dissolution,chloroform or methanol was employed. Thermospray mass spectra (TSMS)were obtained on a Trio-1000 by Fisions spectrometer using 0.1 Mammonium acetate in 1/4 water/methanol. The protonated parent ion isreported as (M+1)⁺. For initial sample dissolution chloroform ormethanol were employed. TLC analyses were performed using E. MerckKieselgel 60 F254 silica plates visualized (after elution with theindicated solvent(s)) by UV, iodine or by staining with 15% ethanolicphosphomolybdic acid or ceric sulfate/ammonium molybdate and heating ona hot plate. The terms “concentrated” and “coevaporated” refer toremoval of solvent at water aspirator pressure on a rotary evaporatorwith a bath temperature of less than 40° C.

The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

General Procedure A (Peptide coupling using DEC). A 0.2-0.5 M solutionof the primary amine (about 1.0 equivalent) in dichloromethane (or aprimary amine hydrochloride and about 1.0-1.3 equivalents oftriethylamine) was treated sequentially with about 1.0-1.2 equivalentsof the carboxylic acid coupling partner, about 1.5-1.8 equivalents of1-hydroxy-7-azabenzotriazole (HOAT) and about 1.0-1.2 equivalents1,2-diethylaminoethyl chloride hydrochloride (DEC) and the mixture wasstirred for about 18-48 hours in an ice bath (the ice bath was allowedto warm, thus the reaction mixture was typically held at about 0-20° C.for about 4-6 hours and about 20-25° C. for the remaining period). Themixture was diluted with ethyl acetate or other solvent as specified,and the resulting mixture washed 1-2 times with 1 N NaOH or saturatedsodium bicarbonate (the aqueous phase being sometimes back-washed withethyl acetate), once with brine, dried over Na₂SO₄, and concentratedgiving the crude product which was purified as specified. The carboxylicacid component could be used as the dicyclohexylamine salt in couplingto the primary amine or hydrochloride of the latter, in which case notriethylamine was employed.

General Procedure B (Peptide coupling using EDC). A 0.04-0.5 M solutionof the primary amine (about 1.0 equivalent) in dichloromethane (or aprimary amine hydrochloride and about 1.0-1.3 equivalents oftriethylamine) was treated sequentially with about 1.0-1.2 equivalentsof the carboxylic acid coupling partner, about 1.5-1.8 equivalents of1-hydroxy-7-azabenzotriazole (HOAT), and about 1.0-1.2 equivalents of(stoichiometrically equivalent to the quantity of carboxylic acid)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) andthe mixture was stirred for about 18-48 hours in an ice bath (the icebath was allowed to warm, thus the reaction mixture was typically heldat about 0-20° C. for about 4-6 hours and about 20-25° C. for theremaining period). The mixture was diluted with chloroform or othersolvent as specified, and the resulting mixture washed twice with 10%HCl (if the product does not contain a basic functionality that wouldmake the compound soluble in aqueous acidic solution), twice withsaturated sodium bicarbonate solution, 1-2 times with brine, dried overanhydrous magnesium sulfate, and concentrated giving the crude productwhich was purified as specified. The carboxylic acid component could beused as the dicyclohexylamine salt in coupling to the primary amine orhydrochloride of the latter, in which case no triethylamine wasemployed.

General Procedure C. (Cleavage of a t-BOC-protected amine usingconcentrated HCl). The t-Boc amine was dissolved in a minimum volume ofethanol and the resulting solution was cooled to about 0° C. andconcentrated HCl (typically about 1-4 mL per mmol amine) was added andthe reaction was warmed to room temperature and stirred for about 1-2.5hours (the time required for complete disappearance of the startingmaterial to a more polar product as judged by TLC). The resultingsolution or suspension was concentrated, and the residue coevaporatedseveral times with added ethanol to give the free amine which was usedwithout further purification or purified as specified.

General Procedure D. (Cleavage of a t-BOC-protected amine using TFA).Trifluoroacetic acid (usually at about 0-25° C.) was added to the t-Bocamine (typically about 10 mL per mmol amine) neat or dissolved in aminimum volume of dichloromethane and the resulting solution was stirredat about 0° C. or at room temperature for 0.25-2 hours (the timerequired for complete disappearance of the starting material to a morepolar product as judged by TLC). The resulting solution or suspensionwas concentrated, and the residue coevaporated several times with addedmethylene chloride. The residue was then dissolved in ethyl acetate andwashed twice with 1 N NaOH and once with brine. The organic phase wasthen dried over Na₂SO₄ and evaporated to give the free amine which wasused without further purification or purified as specified.

General Procedure E. (Cleavage of a benzyl-protected amine using 10%palladium on carbon). The benzyl amine, ethanol (typically about 1 mLper every 0.03-0.08 mmol of amine), and 10% palladium on carbon(typically about 20-100% of the weight of the amine used) were combinedand hydrogenated at about 40-50 psi hydrogen on a Parr® shakerovernight. The mixture was then filtered through a bed of Celite®. TheCelite® was washed with ethanol, and the filtrate was concentrated invacuo to give the de-benzylated amine which was used without furtherpurification or purified as specified.

General Procedure F. (Cleavage of a CBZ-protected amine using 10%palladium on carbon) The CBZ amine, ethanol (typically about 1 mL perevery 0.03-0.08 mmol of amine), and 10% palladium on carbon (typicallyabout 20-100% of the weight of the amine used) were combined andhydrogenated at about 40-50 psi hydrogen on a Parr® shaker overnight.The mixture was then filtered through a bed of Celite®. The Celite® waswashed with ethanol, and the filtrate was concentrated in vacuo to givethe de-benzylated amine which was used without further purification orpurified as specified.

EXAMPLE 12-Amino-N-[2-(8a(S)-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1(R)-(3,5-dichloro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 2-Benzyl-piperazine-1,2,4-tricarboxylic Acid 1-Benzyl Ester4-tert-Butyl Ester 2-Methyl Ester

To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzylester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol), prepared asdescribed by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), intetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). Thereaction was cooled to about −78° C., and a 1M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. Thereaction was stirred at about −78° C. for about 1 hour, and then benzylbromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about30 minutes more at about −78° C., then warmed to room temperature andstirred overnight. The reaction was quenched with saturated sodiumbicarbonate solution, and the mixture was extracted three times withethyl acetate. The combined organic layers were extracted twice withwater, brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give 31 g of crude product. Purification bysilica gel chromatography using 10-20% ethyl acetate/hexanes as eluentafforded the title compound of part 1-A (20.33 g, 82%): +APcl MS (M−55)⁺413, (M−99)⁺ 369; ¹H NMR=400 MHz (CDCl₃) δ: 7.37 (arom, m, 5H), 7.22(arom, m, 3H), 7.00 (arom, m, 2H), 1.41 (BOC, d, 9H).

B. 8a-Benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acidtert-Butyl Ester

To a stirred solution of the title compound of part 1-A (18.06 g, 38.5mmol) in tetrahydrofuran (180 mL) cooled to about 0° C. was added a 1Msolution of lithium triethylborohydride in tetrahydrofuran (86.8 mL)over about 10 min. The reaction was allowed to warm to room temperaturefor about 1 hour, after which an additional 5 mL of the 1M solution oflithium triethylborohydride was added. The reaction was stirred forabout 30 minutes at room temperature, then quenched with saturatedsodium bicarbonate solution followed by the addition of 1 N HClsolution. The mixture was then extracted three times with ethyl acetate.The combined organic layers were extracted with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to give 20.4 g of a dearoil. Purification by silica gel chromatography using 5% methanol/ethylacetate as eluent afforded 13 g of a solid. Trituration of the solidwith ethyl ether afforded the title compound of part 1-B (9.50 g, 74%):+APcl MS (M−55)⁺ 277, (M−99)⁺ 233; ¹H NMR=400 MHz (methanol-d₄) δ:7.30-7.23 arom, m, 5H), 4.11 (—CO₂CH ₂ 13 , d of d, 2H), 1.50 (BOC, s,9H).

C. 8a-Benzyl-hexahydro-oxazolo[3,4-a]pyrazin-3-one, Hydrochloride

The title compound of part 1-B (9.5 g, 28.6 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of part 1-C (7.90 g, ca 100%): +APcl MS (M+1)⁺ 233; ¹HNMR=400 MHz (methanol-d₄) δ: 7.32-7.23 (arom, m, 5H), 4.22 (—CO₂CH ²—, dof d, 2H).

D. 2-tert-Butoxycarbonylamino-2-methyl-propionic Acid2,5-Dioxo-pyrrolidin-1-yl Ester

A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol),N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) inanhydrous dichloromethane (1.4 L) was stirred at room temperature forabout 18 hours under nitrogen atmosphere. The reaction mixture waswashed three times each with saturated sodium bicarbonate solution andthen brine. The organic layer was dried over sodium sulfate, filteredand concentrated in vacuo to give the title compound of part 1-D as awhite solid (256 g, 88%): PBMS (M+18)⁺ 318; ¹H NMR=250 MHz (CDCl₃) δ:4.91 (NH, br s, 1H), 2.84 (—CO(CH ₂)₂CO—, s, 4H), 1.67 (Me, s, 6H), 1.48(BOC, s, 9H).

E. 2-tert-Butoxycarbonylamino-3-(3,5-dichloro-benzyloxy)-propionic Acid

To a stirred solution of N-t-butoxycarbonyl-D-serine (10.0 g, 48.7 mol)in N,N-dimethylformamide (150 mL) at about 0° C. was added sodiumhydride (4.0 g, 60% dispersion in mineral oil, 99.84 mmol) portionwise.The mixture was stirred for about 30 minutes, and then a solution of1,3-dichloro-5-chloromethyl-benzene (9.5 mL, 48.7 mmol) in ethyl ether(40 mL) was added. The reaction was allowed to slowly warm to roomtemperature overnight. The reaction was then quenched with 1 N NaOH, themixture extracted three times with dichloromethane. The combined organiclayers were then washed three times with water, 1 N HCl, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to givecrude product. The original basic aqueous layer was then acidified toabout pH 4 with 1 N HCl, and the mixture was extracted three times withdichloromethane. These three organic layers were combined and washedthree times each with water and brine then dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give anadditional 620 mg of crude product. Both product fractions were combinedand purified by silica gel chromatography using 5% methanol/chloroformas eluent and yielded the title compound of part 1-E (12.39 g, 70%):−APcl MS (M−1)⁻363, (M−3)⁻361; ¹H NMR=400 MHz (CDCl₃) δ: 7.13 (arom, s,3H), 5.42 (NH, d, 1H), 4.50 (CHCO₂H, m, 1H), 4.45 (PhCH ₂O, s, 2H), 3.82(CH ₂OBz, d of d, 2H), 1.43 (BOC, s, 9H).

F. 2-Amino-3-(3,5-dichloro-benzyloxy)-propionic Acid, Hydrochloride

The title compound of part 1-E (12.39 g, 34.02 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of part 1-F (9.52 g, 93%): −APcl MS (M−1)⁻ 263; ¹HNMR=400 MHz (methanol-d₄) δ: 7.35 (arom, m, 3H), 4.59 (PhCH ₂O, s, 2H),4.17 (CHCO₂H, m, 1H), 3.93 (CH ₂OBz, m, 2H).

G.2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(3,5-dichloro-benzyloxy)-propionicAcid

A stirred solution of the title compound of part 1-F (9.52 g, 31.67mmol), the title compound of part 1-D (9.5 g, 31.67 mmol), andtriethylamine (13.24 mL, 95.01 mmol) in dioxane/water (100 mL/25 mL) washeated to about 50° C. for about 3 days. The reaction mixture was thenconcentrated in vacuo, diluted with 1 N HCl, and then extracted threetimes with aqueous 10% HCl until the mixture was at pH 2.

The organic layer was washed with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the title compound of part1-G: −APcl MS (M−1)⁻ 448, (M−2)⁻ 447; ¹H NMR=400 MHz (CDCl₃) δ: 7.15(arom, m, 3H), 5.12 (NH, br s, 1H), 4.64 (CHCO₂H, m, 1H), 4.45 (PhCH ₂O,s, 2H), 3.70 (CH ₂OBz, d of d, 2H), 1.49 (Me, s, 3H), 1.48 (Me, s, 3H),1.38 (BOC, s, 9H).

H.{1-[2-(8a(S)-Benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1(R)-(3,5-dichloro-benzyloxymethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure A, the title compound of part 1-C (0.15g, 0.56 mmol) was coupled to the title compound of part 1-G (0.25 g,0.56 mmol), and the product was purified by silica gel chromatographyusing ethanol/ethyl acetate/hexanes (1:50:40) as eluent to give the lesspolar isomer the title compound of part 1-H (153 mg, 41%): +APcl MS (M)⁺663, (M+2)⁺ 665, (M−98)⁺ 565, (M−100)⁺ 563; ¹H NMR=400 MHz (CDCl₃) δ:7.23-7.10 (arom, m, 8H), 4.41 (PhCH ₂O, AB, 2H), 1.42 (Me, s, 3H), 1.38(Me, s, 3H), 1.29 (BOC, s, 9H).

I.2-Amino-N-[2-(8a(S)-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1(R)-(3,5-dichloro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The title compound of part 1-H (153 mg, 0.230 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of this Example 1 (128 mg, 93%): +APcl MS (M)⁺ 563,(M+2)⁺ 565; ¹H NMR=400 MHz (methanol-d₄) δ: 7.30-7.24 (arom, m, 8H),4.54 (PhCH ₂O, s, 2H), 1.58 (Me, s, 3H), 1.57 (Me, s, 3H).

EXAMPLE 22-Amino-N-[2-(8a(S)-benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 3-Benzyl-piperazine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-MethylEster

The title compound of part 1-A (2.80 g, 5.98 mmol) was deprotectedaccording to the method described in General Procedure F to give thetitle compound of part 2-A as a white foam (1.89 g, 95%): +APcl MS(M+1)⁺ 335, (M−55)⁺ 279, (M−99)⁺ 235; ¹H NMR=400 MHz (CDCl₃) δ:7.28-7.18 (arom, m, 5H), 3.66 (Me, s, 3H), 1.40 (BOC, s, 9H).

B. 3,4-Dibenzyl-piperazine-1,3-dicarboxylic Acid 1-tert-Butyl Ester3-Methyl Ester

To a solution of the title compound of part 2-A (1.22 g, 3.65 mmol) anddiisopropylamine (0.63 mL, 3.65 mmol) in acetonitrile (18 mL) was addedbenzyl bromide (0.45 mL, 3.83 mmol), and the reaction was stirred atroom temperature overnight. The reaction was then heated to reflux forabout 5 hours. The solvent was then removed in vacuo, and ether wasadded to the residue. The solid precipitate was removed by filtration,and the filtrate was concentrated in vacuo to give the title compound ofpart 2-B as a colorless oil (0.87 g, 56%): ¹H NMR=400 MHz (CDCl₃) δ:7.32-7.13 (arom, m, 10H), 3.65 (Me, s, 3H), 1.37 (BOC, s, 9H).

C. 3,4-Dibenzyl-3-hydroxymethyl-piperazine-1-carboxylic Acid tert-ButylEster

To a solution of the title compound of part 2-B (0.87 g, 2.05 mmol) intetrahydrofuran (10 mL) was added a 1M solution of lithiumtriethylborohydride in tetrahydrofuran (4.1 mL), with immediateeffervescence observed. The reaction was stirred for about 30 minutes,after which an additional 0.5 mL of the 1M solution of lithiumtriethylborohydride was added. The reaction was then quenched with a 1 NHCl solution (0.5 mL). The mixture was stirred for about 5 minutes, thenbasified with 1 N NaOH. The mixture was extracted three times with ethylacetate. The combined organic layers were extracted with brine, driedover sodium sulfate, filtered and concentrated in vacuo to give thetitle compound of part 2-C as a clear oil (0.80 g, 99%): +APcl MS (M+1)⁺397, (M−55)⁺ 341, (M−99)⁺ 297; ¹H NMR=300 MHz (CDCl₃) δ: 7.31-7.25(arom, m, 10H), 1.50 (BOC, s, 9H).

D. 3,4-Dibenzyl-3-formyl-piperazine-1-carboxylic Acid tert-Butyl Ester

To a stirred solution of DMSO (0.312 mL, 4.44 mmol) in dichloromethane(10 mL) cooled to about −78° C. was slowly added oxalyl chloride (0.193mL, 2.22 mmol), followed by a solution of the title compound of part 2-C(0.80 g, 2.0 mmol) in dichloromethane (3 mL). The reaction was thenallowed to warm to about −30° C. and was stirred for about 30 minutes.The reaction was re-cooled to about −78° C., and triethylamine (1.40 mL,10.1 mmol) was slowly added. The reaction was stirred for about 5minutes at about −78° C., then was allowed to warm to room temperature.The reaction was quenched with water and the mixture was extractedseveral times with dichloromethane. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to give the title compound of part 2-D as a clear oil (777 mg,97%): +APcl MS (M)⁺ 394, (M−56)⁺ 338, (M−100)⁺ 294; ¹H NMR=300 MHz(CDCl₃) δ: 9.72 (aldehyde, s, 1H), 7.30-7.22 (arom, m, 10H), 1.40 (BOC,s, 9H).

E. 3,4-Dibenzyl-3-methylaminomethyl-piperazine-1-carboxylic Acidtert-Butyl Ester

To a stirred solution of the title compound of part 2-D (0.34 g, 0.86mmol) in methanol (4 mL) cooled to about 0° C. was slowly addedmethylamine hydrochloride (0.29 g, 4.3 mmol), followed by sodium acetate(0.707 g, 8.63 mmol), 3 Å molecular sieves (0.34 g), and sodiumcyanoborohydride (0.064 g, 1.03 mmol). The reaction was allowed to warmto room temperature and was stirred overnight. The mixture was thenfiltered through a bed of Celite®. The Celite® was washed with methanol,and the filtrate was concentrated in vacuo. The residue was diluted withethyl acetate, and the mixture was extracted twice with 1 N NaOH, brine,dried over sodium sulfate, filtered and concentrated in vacuo to give340 mg of a clear oil. Purification by silica gel chromatography using4% methanol/dichloromethane as eluent afforded the title compound ofpart 2-E as a clear oil (214 mg, 61%): +APcl MS (M+1)⁺ 410, (M−55)⁺ 354,(M−99)⁺ 310; ¹H NMR=400 MHz (CDCl₃) δ: 7.32-7.24 (arom, m, 10H), 2.30(NMe, s, 3H), 1.50 (BOC, s, 9H).

F. 3-Benzyl-3-methylaminomethyl-piperazine-1-carboxylic Acid tert-ButylEster

The title compound of part 2-E (0.21 g, 0.51 mmol), methanol (15 mL),and palladium hydroxide on carbon (0.187 g) were combined andhydrogenated at 45 psi H₂ on a Parr® shaker for approximately 2 days.The mixture was then filtered through a bed of Celite®. The Celite® waswashed with ethanol, and the filtrate was concentrated in vacuo to give180 g of a clear oil. Purification by silica gel chromatography usingammonium hydroxide/methanol/chloroform (0.25:5:95) as eluent yielded thetitle compound of part 2-F as a dear oil (102 mg, 65%): +APcl MS (M+1)⁺320, (M−55)⁺ 264, (M−99)⁺ 220; ¹H NMR=400 MHz (CDCl₃) δ: 7.24-7.17(arom, m, 5H), 2.42 (NMe, s, 3H), 1.40 (BOC, s, 9H).

G.8a-Benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicAcid tert-Butyl Ester

A stirred solution of the title compound of part 2-F (100 mg, 0.31 mmol)and 1,1′-carbonyldimidazole (54 mg, 0.34 mmol) in tetrahydrofuran (3 mL)was heated to reflux for about 2.5 hours, and then allowed to sit atroom temperature overnight. The reaction was quenched with saturatedsodium bicarbonate solution, and extracted three times with ethylacetate. The combined organic layers were extracted with brine, driedover sodium sulfate, filtered and concentrated in vacuo to give 142 mgof crude product. Purification by silica gel chromatography using 67%ethyl acetate/hexanes as eluent yielded the title compound of part 2-Gas a white solid (93 mg, 87%): +APcl MS (M−55)⁺ 290, (M−99)⁺ 246; ¹HNMR=400 MHz (CDCl₃) δ: 7.29-7.21 (arom, m, 5H), 2.68 (NMe, s, 3H), 1.48(BOC, s, 9H).

H. 8a-Benzyl-2-methyl-hexahydro-imidazo[1,5-a]pyrazin-3-one,Hydrochloride

The title compound of part 2-G (89 mg, 0.258 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of part 2-H (77 mg, 77%): +APcl MS (M+1)⁺ 246; ¹H NMR=400MHz (CDCl₃) δ: 7.28 (arom, m, 5H), 4.40-2.82 (series of m, 10H), 2.70(NMe, s, 3H).

I.3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicAcid

To a solution of D-O-benzylserine (106 g, 0.532 mol) and the titlecompound of part 1-D (160 g, 0.532 mol) in water/dioxane (250/1000 mL)was slowly added triethylamine (223 mL, 1.60 mol) at room temperature.The reaction was heated to about 50° C. and stirred for about 15 hoursunder nitrogen atmosphere. The solvent was then removed in vacuo, ethylacetate was added, and the stirred mixture was acidified with 10%aqueous HCl solution to pH 2-3. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to give the title compoundof part 2-I (200 g, 99%): −APcl MS (M−1)⁻ 379; ¹H NMR=300 MHz(methanol-d₄) δ: 7.69 (NH, d, 1H), 7.32 (Ph, m, 5H), 4.60 (CHCO₂H, m,1H), 4.51 (CHH₂Ph, s, 2H), 3.81 (CHH₂OBz, m, 2H), 1.41 (Me, s, 6H), 1.40(BOC, s, 9H).

J.{1-[2-(8a(S)-Benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure A, the title compound of part 2-H (39 mg,0.14 mmol) was coupled toD-O-benzylserine-N-t-butoxycarbonyl-a-methylalanine (53 mg, 0.14 mmol),and the product was purified by silica gel chromatography using ethylacetate as eluent to give the title compound of part 2-J (23 mg, 27%):+APcl MS (M+1)⁺ 608, (M−99)⁺ 508; ¹H NMR=400 MHz (CDCl₃) δ: 7.28-7.12(arom, m, 10H), 5.28 (PhCHH₂O, s, 2H), 2.65 (NMe, s, 3H), 1.44 (Me, s,3H), 1.42 (Me, s, 3H), 1.32 (BOC, s, 9H).

K.2-Amino-N-[2-(8a(S)benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamideHydrochloride

The title compound of part 2-J (23 mg, 0.038 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of this Example 2 as a clear glass (206 mg, 92%): +APclMS (M+1)⁺ 508; ¹H-NMR=400 MHz (methanol-d₄) δ: 7.23 (arom, m, 10H), 4.52(PhCHH₂O, s, 2H), 2.58 (NMe, s, 3H), 1.57 (Me, s, 6H).

EXAMPLE 32-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

A. 2-Pyridin-2-ylmethyl-piperazine-1,2,4-tricarboxylic Acid 1-BenzylEster 4-tert-Butyl Ester 2-Methyl Ester

A stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester4-tert-butyl ester 2-methyl ester (200 g, 529 mol), prepared asdescribed by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), intetrahydrofuran (200 mL) and DMF (1.5 L) was cooled to about −78° C.,and a 0.5 M solution of potassium bis(trimethylsilyl)amide in THF (1.27L) was added. After the above solution had stirred for about one hour,the free base of 2-picolyl chloride was generated by extracting thecorresponding hydrochloride salt (217 g, 1.32 mol) from saturated sodiumbicarbonate solution with methylene chloride. The combined organicextracts were dried (MgSO₄), concentrated, immediately dissolved in DMF(100 mL), and then added dropwise to the enolate containing solution.The reaction was stirred for about 4 hours at about −78° C., then slowlywarmed to room temperature and stirred overnight. The toluene and THFwere removed under reduced pressure. The residue was extracted fromwater (1.5 L) with ethyl acetate (3×1 L), the combined extracts werethen washed with water (1.5 L), dried (MgSO₄) and then concentrated invacuo to give 240 g of crude product of the title compound of part 3-Awhich was carried on to the next step: +APcl MS (M+H)⁺ 470, (M−^(t)Bu+H)436; ¹H NMR=400 MHz (methanol-d₄) δ: 8.4 (arom, m, 1H), 7.65-7.2 (arom,m, 7H), 6.94 (arom, m, 1H), 5.18 (CbzNCHH, m, 1H), 5.05 (CbzNCHH, m,1H), 2.54 (m, 1H), 1.41 (Boc, s, 9H).

B. 3-Pyridin-2-ylmethyl-piperazine-1,3-dicarboxylic Acid 1-tert-ButylEster 3-Methyl Ester

The crude Cbz amine, the title compound of part 3-A, (240 g) in methanol(1 L), and 10% palladium on carbon (10 g, added in 100 mL water) werecombined and hydrogenated at about 40-50 psi hydrogen on a Parr® shakerfor about 2 days. The mixture was then filtered through a bed ofdiatomaceous earth. The diatomaceous earth was washed with ethanol, andthe filtrate was concentrated in vacuo to give the de-benzylated amine.Two of the above alkylation/reductions were combined and purified bysilica gel chromatography using 1:1 ethyl acetate/hexanes to ethylacetate to 1:9 methanol/ethyl acetate as eluent and yielded the titlecompound of part 3-B (217 g, 61%): +APcl (M+1)⁺ 336; ¹H NMR=400 MHz(methanol-d₄) δ: 8.45 (arom, d, 1H), 7.72 (arom, t, 1H), 7.26-7.11(arom, m, 2H), 4.38 (br s, 1H), 3.57 (MeO, s, 3H), 1.41 (Boc, s, 9H).

C.1,3-Dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicAcid tert-Butyl Ester

To a suspension of N,N′-carbonyldiimidazole (69 g, 426 mmol) and2,2,2-trifluoro-ethylamine hydrochloride (71 g, 527 mmol) indichloromethane (500 mL) was added triethylamine (76 mL, 544 mmol) atabout 0° C. dropwise. The reaction was then warmed to room temperatureand stirred at room temperature for about 30 minutes. A solution of thetitle compound of part 3-B (57 g, 170 mmol) in dichloromethane (100 mL)was then added, and the reaction was heated to about 40° C. and thenstirred for approximately 2 days. The reaction was quenched withsaturated sodium bicarbonate solution, and the mixture was thenextracted twice with dichloromethane. The combined organic layers wereextracted twice with water, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give crude product. Purificationby silica gel chromatography using 1:9 to 1:2 to 1:1 ethylacetate/hexanes as eluent afforded the title compound of part 3-C (68.3g, 94%) as an amorphous solid: +APcl MS (M+H)⁺ 429; ¹H NMR=400 MHz(CDCl₃) δ: 8.4 (arom, d, 1H), 7.54 (arom, t, 1H), 7.12 (arom, t, 1H),7.04 (arom, d, 1H), 4.16-4.00 (CF₃CH₂, m, 2H), 3.41 (PyrCH ₂, Ab_(q),2H), 1.50 (Boc, s, 9H).

D.8a-Pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione

The title compound of part 3-C (22.8 g, 53.2 mmol) was deprotectedaccording to he method described in General Procedure C to give a pinksolid. The residue was extracted from saturated aqueous NaHCO₃ withmethylene chloride, the combined organic layers were washed with brine,dried (MgSO₄) and concentrated to give the title compound of part 3-D asa light yellow solid (13.7 g, 78%): +APcl MS (M+H)⁺ 329; ¹H NMR=400 MHz(CDCl₃) δ: 8.42 (arom, ddd, 1H), 7.55 (arom, td, 1H), 7.37-7.07 (arom,m, 2H); 4.15-3.98 (CF₃CH ₂, m, 2H), 3.87 (NCHHCH₂, m, 1H), 3.79 (CCHHNH,d, 1H), 3.40 (CCHHNH, d, 1H), 3.25 (PyrCHH, d, 1H), 3.13 (NCHHCH₂, ddd,1H), 3.02 (NCH₂CHHNH, dd, 1H), 2.74 (PyrCHH, d, 1H), 2.66 (NCH₂CHHNH,td, 1H).

E.(1-{1(R)-Benzyloxymethyl-2-[1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

According to General Procedure B, 3-D (5.6 g, 15.4 mmol) was coupled tothe title compound of part 2-I (5.84 g, 15.4 mmol), and the product waspurified by silica gel chromatography using 2:1 ethyl acetate/hexanes aseluent to give the title compound of part 3-E (34513-284-1) as acolorless solid (7.3 g, 69%): +APcl MS (M+H)⁺ 691; ¹H NMR 400 MHz(CDCl₃) δ: 8.35 (arom, m, 1H), 5.23-5.10 (m, 2H), 2.60 (t, 1H).

F.2-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

The title compound of part 3-E (410 mg, 0.59 mmol) was deprotectedaccording to the method described in General Procedure C to give acolorless solid (6.23 g, 94%).

HPLC separation of the isomers provided the shorter retained isomer(2.65 g, 85%): A 70×500 mm Inertsil 15 micron C-8 column (PhenomenexInc, 2320 W. 205th St., Torrance, Calif. 90501) was equilibrated with100% 0.050M KH₂PO₄ adjusted pH 2.20 with H₃PO₄. The sample was dissolvedin 20 ml mobile phase along with a few drops of H₃PO₄ and was injectedonto the column. The column was eluted at 237.5 ml/min., 100% buffer for1 min., ramped to 75% buffer 25% CH₃CN in 12.5 min., and then held for21.5 min. (total run time 35 min.). The column was then rinsed off with50% water 50% CH₃CN. The product was observed at 254 nm, and was foundin fractions 7-11 (24-29 min.). These fractions were combined, adjustedto a pH of about 7.5 with NaHCO₃ and then extracted with CHCl₃ (2×1000ml). The organics were combined, dried (Na₂SO₄) and concentrated to acolorless foam (86.5% diastereomer excess).

HPLC analysis was performed on an Hewlett-Packard 1050 system with a1050 DAD, autosampler and solvent delivery system (Hewlett-PackardCompany, Analytical Business Center, 2850 Centerville Road, Wilmington,Del. 19808-1610). Data was imported into a HP Vectra XM series 3 runningHP Chemstation ver A.4.02. A 10 μL sample dissolved in the mobile phaseat 1 mg/ml was injected for analysis. A Prodigy 3.2×250 mm 5 micron C-8column (Phenomenex Inc, 2320 W. 205th St., Torrance, Calif. 90501) wasemployed with the following solvents: A=0.050 M KH₂PO₄ adjusted to pH2.20 with H₃PO₄; C=acetonitrile. An isocratic elution was employed using65% A and 35% C with a flow rate of 0.5 ml/min. detecting at uv, 254 nm.The desired enantiomer eluted at 5.7 min., while the less desiredenantiomer eluted at 6.3 min.

The desired enantiomer was taken up in ethanol (150 mL), slowly treatedwith concentrated aqueous HCl (75 mL) at about 0° C., and the solventthen removed under reduced pressure. The residue was then concentratedfrom ethanol (4×) to remove residual, water. The product was trituratedwith ethyl ether to give the title compound of this Example 3 (2.72 g,97%): +APcl MS (M+H)⁺ 591; ¹H NMR=400 MHz (methanol-d₄) δ: 8.83-6.90 (NHand arom, series of m, 10H), 5.18-2.90 (aliphatic, series of m, 15H),1.59 (Me, s, 6H); ¹³C NMR=100 MHz (methanol-d₄) δ: 172.4, 148.1, 143.4,130.3, 129.5, 129.0, 127.7, 74.4, 69.7, 64.6, 58.2, 52.3, 47.9, 46.9,40.8, 40.5, 39.2, 36.0, 24.2, 24.1.

EXAMPLE 3a2-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

8a(S)-Pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione

To a solution of the title compound of part 3-D (206 g, 628 mmol) in10:1 acetone/water (4.5 L) was added D-tartaric acid (94.2 g, 628 mmol).After several minutes a colorless precipitate formed. After stirring forabout 2 days the solid was collected by filtration (144 g, 80% ee). Theprecipitate was then placed in acetone (2 L) and was heated for about 15hours at about 55° C. The mixture was cooled and the solid collected byfiltration (117 g, 94% ee). The tartrate salt was then extracted fromaqueous sodium bicarbonate with 3:1 chloroform/isopropanol to give thefree base 3a-A (81.7 g, 78% ee) as an off-white solid. HPLC analysis ofthe title compound of part 3a-A indicated that the material had anenantiomeric excess of 96%: +APcl MS (M+H)⁺ 329.

HPLC analysis was performed on an Hewlett-Packard 1050 system with a1050 DAD, autosampler and solvent delivery system. Data was importedinto a HP Vectra XM series 3 running HP Chemstation ver A.4.02. Whenpossible, samples were dissolved in the mobile phase at 1 mg/ml. AChiracel AD 4.6×250 mm column (Chiral Technologies, 730 SpringfieldDrive, P.O. Box 564, Exton Pa. 19341) was employed with the followingsolvents: A=hexane+0.1% diethylamine (v/v); C=isopropanol+0.1%diethylamine (v/v). An isocratic elution was employed using 85% A and15% C with a flow rate of 1 ml/min, detecting at uv, 254 nm. The desiredenantiomer eluted at 11.8 min., while the less desired enantiomer elutedat 15.6 min.

B.(1-{1(R)-Benzyloxymethyl-2-[1,3-dioxo-8a(S)-Pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

To a solution of the title compound of part 3a-A at about 0° C. (10.0 g,30.5 mmol) and the title compound of part 2-I (13.9 g, 36.6 mmol) inethyl acetate (200 mL) was added triethylamine (17 mL, 122 mmol),followed by slow addition of a 50% solution of 1-propanephosphonic acidcyclic anhydride in ethyl acetate (18.1 mL, 30.5 mmol) and the reactionwas allowed to warm to room temperature. After about 15 hours, thereaction was extracted from saturated aqueous sodium bicarbonate withethyl acetate, the combined organics were washed with water and thenbrine, dried (MgSO₄), concentrated in vacuo, and the product thenpurified by silica gel chromatography using 0% to 1% to 5% methanol inchloroform as eluent to give the title compound of part 3a-B (19.5 g,92%) as a colorless foam.

C.2-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-)propionamide,Hydrochloride

The title compound of part 3-E (17.5 g, 25.3 mmol) was deprotectedaccording to the method described in General Procedure C to give acolorless solid. The product was triturated with ethyl ether to give thetitle compound of this Example 3a (13.6 g, 90%): +APcl MS (M+H)⁺ 591.

EXAMPLE 42-Amino-N-[2-(8a(S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide

A.8a-Benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicAcid tert-Butyl Ester

To a solution of the title compound of part 2-A (676 mg, 2.02 mmol) inacetone (3 mL) was added methyl isocyanate (0.300 mL, 5.09 mmol). Thereaction was heated to a gentle reflux and stirred overnight undernitrogen atmosphere. The reaction was quenched with methanol (1 mL), andthe mixture was concentrated in vacuo. Purification by silica gelchromatography using 50% ethyl acetate/hexanes as eluent afforded 607 mgof crude product, which was recrystallized in ethanol (0.5 mL) to givethe title compound of part 4-A: +APcl MS (M+1)⁺ 360; ¹H NMR=300 MHz(CDCl₃) δ: 7.20 (arom., m, 3H), 7.04 (arom., m, 2H), 1.52 (BOC, s, 9H).

B. 8a-Benzyl-2-methyl-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione

The title compound of part 4-A (150 mg, 0.416 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of part 4-B (113 mg, 92%), MS (APCI) 260.2.

C.{1-[2-(8a(S)-Benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure A, the title compound of part 4-B (101mg, 0.342 mmol) was coupled to the title compound of part 2-I (130 mg,0.342 mmol), and the product was purified by silica gel chromatographyusing methylene chloride with a 0-10% methanol gradient as eluent togive the title compound of part 4-C (88 mg, 41%), MS (PB) 622.

D.2-Amino-N-[2-(8a(S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide

The title compound of part 4-C (82 mg, 0.132 mmol) was deprotectedaccording to the method described in General Procedure C, and theproduct was triturated with ethyl ether to give the title compound ofthis Example 4 (61 mg, 89%). +APcl MS (M+1)⁺ 522.3.

EXAMPLE 52-Amino-N-[1-benzyloxymethyl-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. Piperazine-1,3-dicarboxylic Acid 1-tert-Butyl Ester 3-Methyl Ester

According to General Procedure F, piperazine-1,2,4-tricarboxylic acid1-benzyl ester 4-tert-butyl ester 2-methyl ester (3.0 g, 7.9 mmol) wasdeprotected to give the title compound of part 5-A (1.8 g, 94%): +APclMS (M+H)⁺ 245; ¹H NMR=400 MHz (CDCl₃) δ: 3.73 (Me, s, 3H), 3.43 (dd,1H), 2.73 (t, 1H), 1.45 (BOC, s, 9H).

B. 2-Methyl-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione, TrifluoroaceticAcid Salt

To a pre-dried flask was added the title compound of part 5-A (1.0 g,4.1 mmol), triethylamine (3.99 mL, 28.7 mmol) and anhydrousdichloromethane (30 mL). The mixture was cooled to about 0° C., and thena 1.93 M solution of phosgene in toluene (3.18 mL, 6.10 mmol) was added,and the reaction was stirred at about 0° C. for about 30 minutes. A 2 Msolution of methylamine in methanol (3.07 mL, 6.10 mmol) was added, andthe reaction was stirred for about 30 minutes at about 0° C., and thenallowed to warm to room temperature and stirred overnight. The reactionwas quenched with saturated sodium bicarbonate solution, and the mixturewas then extracted three times with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 0.85 g oft-BOC-protected amine product. The above t-BOC-protected amine productwas deprotected according to the method described in General Procedure Dto give the title compound of part 5-B as the trifluoroacetic acid salt:+APcl MS (M+H)⁺ 170; ¹H NMR=400 MHz (CDCl₃) δ: 4.45 (dd, 1H), 4.36 (dd,1H), 3.07 (Me, s, 3H).

C.{1-[1(R)-Benzyloxymethyl-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure B. the title compound of part 5-B (50 mg,0.18 mmol) was coupled to the title compound of part 2-I (60 mg, 0.16mmol), and the product was purified by silica gel chromatography usingchloroform to 3% methanol/chloroform as eluent to give the titlecompound of part 5-C (46 mg, 42%) as a colorless foam: +APcl MS (M+H)⁺532; ¹H NMR=400 MHz (CDCl₃) δ: 7.37-7.20 (arom, m, 5H), 7.02 (CHNH, d,1H), 3.00 (Me, s, 1H), 2.96 (Me, s, 2H).

D.2-Amino-N-[1(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The title compound of part 5-C (46 mg, 0.090 mmol) was deprotectedaccording to the method described in General Procedure C, and theproduct was triturated with ethyl ether to give the title compound ofthis Example 5 (33 mg, 82%): +APcl MS (M+1)⁺ 432; ¹H NMR=400 MHz (CDCl₃)δ: 8.70-8.60 (NH, br m, 1H), 2.99 (Me, s, 1H), 2.97 (Me, s, 2H).

EXAMPLE 62-Amino-N-{1-benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

A. 2-(4-Fluoro-benzyl)-piperazine-1,2,4-tricarboxylic Acid 1-BenzylEster 4-tert-Butyl Ester 2-Methyl Ester

Alkylation of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester4-tert-butyl ester 2-methyl ester (10.2 g, 27.0 mmol) with2-fluorobenzyl bromide (5.11 g, 27.0 mmol) was performed analogous tothe preparation of the title compound of part 1-A to afford the titlecompound of part 6-A (2.78 g, 21%): +APcl MS (M−Boc+H)⁺ 387; ¹H NMR=400MHz (CDCl₃) δ: 7.45-7.30 (arom, br s, 5H), 7.00-6.80 (arom, br m, 4H),5.35-5.05 (br m, 2H), 2.53 (br t, 1H), 1.40 (Boc, s, 9H).

B. 3-(4-Fluoro-benzyl)-piperazine-1,3-dicarboxylic Acid 1-tert-ButylEster 3-Methyl Ester

According to General Procedure F, the title compound of part 6-A (0.249g, 0.72 mmol) was deprotected to give the title compound of part 6-B(0.230 g, 91%): +APcl MS (M+H)⁺ 353, (M−^(t)Bu+H)⁺ 297, (M−Boc+H)⁺ 253;¹H NMR=400 MHz (CDCl₃) δ: 7.08-6.90 (arom, m, 4H), 3.62 (Me, s, 3H),1.41 (Boc, s, 9H).

C. 4-Acetyl-3-(4-fluoro-benzyl)-piperazine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester

To a solution of the title compound of part 6-B (77 mg, 0.22 mmol) anddiisopropylethylamine (0.15 mL, 0.87 mmol) in dichloromethane (1 mL) wasadded acetyl chloride (0.031 mL, 0.44 mmol). The reaction was stirredfor about 1.5 hours, then quenched with saturated aqueous NaHCO₃.Additional methylene chloride was added and the mixture was washed twicewith saturated NaHCO₃, then brine, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give the crude productthe title compound of part 6-C (86 mg, quantitative): +APcl MS(M−^(t)Bu+H)⁺ 339, (M−Boc+H)⁺ 295; ¹H NMR=400 MHz (CDCl₃) δ: 7.10-7.69(arom., m, 4H), 3.70 (MeO, d, 3H), 2.10 (MeCO, d, 2H), 1.42 (BOC, d,9H).

D.8a-(4Fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicAcid tert-Butyl Ester

To a stirred solution of the title compound of part 6-C (86 mg, 0.22mmol) in anhydrous tetrahydrofuran (1.5 mL) cooled to about −78° C.under nitrogen atmosphere was added a 1M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.66 mL, 0.66 mmol)dropwise. The reaction was stirred at −78° C. for about 10 minutes, thenthe reaction was quenched with methanol and concentrated in vacuo. Ethylacetate was added, and the mixture was extracted with saturated ammoniumchloride solution, brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give crude product. Purificationby silica gel chromatography using 0-50% ethyl acetate/hexanes as eluentyielded the title compound of part 6-D (53 mg, 67%): −APcl MS (M−H)⁻361; ¹H NMR=400 MHz (CDCl₃) δ: 6.94 (arom., d, 4H), 2.66 (CHHPh, d, 1H),2.01 (CHHPh, d, 1H), 1.47 (BOC, s, 9H).

E. 8a-(4-Fluoro-benzyl)-tetrahydro-pyrrolo[1,2-a]pyrazine-6,8-dione,Hydrochloride

The title compound of part 6-D (53 mg, 0.15 mmol) was deprotectedaccording to the method described in General Procedure C, and theproduct was triturated with ethyl ether to give the title compound ofpart 6-E (44 mg, quantitative): +APcl MS (M+1)⁺ 263; ¹H NMR=400 MHz(methanol-d₄) δ: 7.15-6.90 (arom., series of m, 4H), 4.34 (CHHNCO, 1H),2.93 (td, 1H).

F.(1-{1(R)-Benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethylcarbamoyl}-methyl-ethyl)-carbamicAcid tert-Butyl Ester

According to General Procedure B, the title compound of part 6-E (44 mg,0.15 mmol) was coupled to the title compound of part 2-1 (56 mg, 0.15mmol), and the product was purified by silica gel chromatography (0-80%ethyl acetate/hexanes) to give desired isomer of the title compound ofpart 6-F (26 mg, 28%), fractions which contained a mixture of the twodiastereomers (20 mg, 22%), followed by the more polar isomer (6 mg,7%): −APcl MS (M−H)⁻ 623; For 6-F: ¹H NMR=400 MHz (CDCl₃) δ: 7.35-6.85(arom., series of m, 9H), 5.16 (br m, 1H), 2.03 (d, 1H). For isomer ¹HNMR=400 MHz (CDCl₃) δ: 7.35-6.55 (arom., series of m, 9H), 5.24 (br m,1H), 1.91 (d, 1H), 1.40 (Boc, s, 9H).

G.2-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

The title compound of part 6-F (26 mg, 0.042 mmol) was deprotectedaccording to the method described in General Procedure C, and theproduct was triturated with ethyl ether to give the title compound ofthis Example 6 (22 mg, 96%): +APcl MS (M+1)⁺ 525; ¹H NMR=400 MHz(methanol-d₄) δ: 7.40-6.85 (arom., series of m, 9H), 5.15 (t, 1H), 4.54(s, 2H), 2.68 (d, 1H), 1.58 (Me, m, 6H).

EXAMPLE 72-Amino-N-[2-(3a-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 4-Oxo-piperidine-1,3-dicarboxylic Acid 1-tert-Butyl Ester 3-MethylEster

To a mixture of 7.00 g (36.2 mmol) of 4-oxo-piperidine-3-carboxylic acidmethyl ester and 8.82 g (72.3 mmol) of 4,4-dimethylaminopyridine in 200mL of methylene chloride at about 0° C. was added a solution of 7.88 g(36.2 mmol) of di-tert-butyldicarbonate in 150 mL of methylene chlorideover about 30 min. The mixture was warmed to room temperature and thenstirred for about 17 h. The mixture was concentrated and the residue wasdiluted with chloroform and washed three times each with 10% aqueousHCl, saturated aqueous sodium bicarbonate solution and brine, dried overMgSO₄ and concentrated to give 9.18 g of the title compound of part 7-Aas a dear yellow oil.

B. 3-(R,S)-Benzyl-4-oxo-piperidine-1,3-dicarboxylic Acid 1-tert-ButylEster 3-Methyl Ester

To a solution of 5.00 g (19.4 mmol) the title compound of part 7-A in 10mL of DMF was added 745 mg (7.4 mmol) of sodium hydride (60% oildispersion) and the mixture was stirred at room temperature for about 15min. A solution of 3.32 g (19.4 mmol) benzylbromide in 15 mL of DMF wasadded to the stirring solution by cannula and the mixture was stirredfor about 42 h at room temperature. The mixture was diluted with ethylacetate and washed once with water and four times with brine, dried overMgSO₄, and concentrated to give 6.0 g of the title compound of part 7-Bas a yellow oil. MS (Cl, NH₃) 348 (MH⁺).

C. 3-Benzyl-4-methoxycarbonylmethylene-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester

In a pre-dried flask under nitrogen atmosphere was placed trimethylphosphonoacetate (0.97 mL, 6.0 mmol) and anhydrous tetrahydrofuran (5mL). The mixture was cooled to about 0° C., and t-butoxide was addeddropwise over about minutes, and the reaction was stirred about 1 hourat about 0° C. A solution of the title compound of part 7-B (1.058 g,3.049 mmol) in anhydrous tetrahydrofuran (5 mL) was added via syringe,and the reaction was stirred at room temperature overnight. The solventwas removed in vacuo, and aqueous 2N HCl was added and the mixture wasextracted twice with ethyl acetate. The combined organic layers werewashed with saturated sodium bicarbonate and brine and dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo to givethe title compound of part 7-C as a colorless liquid (1.407 g, ca 100%):PBMS (M+1)⁺ 404, (M+18)⁺ 421, (M−55)⁺ 348, (M−99)⁺ 304; ¹H NMR=400 MHz(CDCl₃) δ: 7.25 m, 3H), 7.10 (arom, m, 2H), 5.99 (═CH, br s, 1H), 3.70(Me, s, 3H), 3.60 (Me, s, 3H), 1.40 (BOC, br s, 9H).

D. 3-Benzyl-4-methoxycarbonylmethyl-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester

The title compound of part 7-C (1.4 g, 3.5 mmol), ethyl acetate (25 mL)and 10% palladium on carbon (280 mg) were combined and hydrogenated at50 psi H₂ on a Parr® shaker for about 21 hours. The mixture was thenfiltered through a bed of diatomaceous earth. The diatomaceous earth waswashed with ethyl acetate, and the filtrate was concentrated in vacuo.Purification by silica gel chromatography using 25% ethylacetate/hexanes as eluent afforded the title compound of part 7-D as acolorless liquid (1.09 g, 79%): PBMS (M+1)⁺ 406, (M+18)⁺ 423, (M−99)⁺306; ¹H NMR=400 MHz (CDCl₃) δ: 7.24 (arom, m, 3H), 7.12 (arom, m, 2H),3.69 (Me, s, 3H), 3.57 (Me, s, 3H), 1.42 (BOC, s, 9H).

E. 3-Benzyl-4-carboxymethyl-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester

To a stirred solution of the title compound of part 7-D (1.07 g, 2.64mmol) in methanol (15 mL) at about 0° C. was added a 1M aqueous solutionof lithium hydroxide (3 mL, 3 mmol). The reaction was stirred at roomtemperature overnight, then additional 1M aqueous lithium hydroxidesolution (1.0 mL, 1 mmol) was added.

The reaction was stirred about another 3 hours, then another 1.0 mL ofthe lithium hydroxide solution was added. The reaction was stirred forabout 5 hours more, then concentrated in vacuo. The residue was quenchedwith 2N HCl and extracted four times with ethyl acetate. The combinedorganic layers dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give the title compound of part 7-E as aviscous oil (951 mg, 92%): −APcl MS (M−1)⁻ 390; ¹H NMR=400 MHz (CDCl₃)δ: 7.25 (arom, m, 3H), 7.12 (arom, m, 2H), 3.58 (Me, s, 3H), 1.42 (BOC,s, 9H).

F.3-Benzyl-4-(benzyloxycarbonylamino-methyl)-piperidine-1,3-dicarboxylicAcid 1-tert-Butyl Ester 3-Methyl Ester

A solution of the title compound of part 7-E (951 mg, 2.43 mmol),triethylamine (0.341 mL, 2.46 mmol) and diphenylphosphoryl azide (0.593mL, 2.67 mmol) in benzene under nitrogen atmosphere was heated to refluxfor about 45 minutes. Benzyl alcohol (0.503 mL, 4.86 mmol) was added andthe reaction was refluxed overnight. The reaction was cooled to roomtemperature and the solvent was removed in vacuo. Ethyl acetate wasadded, and the mixture was extracted with water, saturated sodiumbicarbonate solution, brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the title compound of part7-F as a yellow liquid (1.44 g, ca 100%): +APcl MS (M−100)⁺ 397; ¹HNMR=400 MHz (CDCl₃) δ: 7.34-7.12 (arom, m, 10H), 5.09 (NHH, s, 1H), 3.68(PhCH ₂—O, s, 2H), 3.52 (Me, s, 3H), 1,.42 (BOC, br s, 9H).

G. 4-Aminomethyl-3-benzyl-piperidine-1,3-dicarboxylic Acid 1-tert-ButylEster 3-Methyl Ester

The title compound of part 7-F (1.4 g, 2.8 mmol), ethyl acetate (20 mL)and 10% palladium on carbon (280 mg) were combined and hydrogenated atabout 50 psi H₂ on a Parr® shaker for about 20 hours. The mixture wasthen filtered through a bed of diatomaceous earth. The diatomaceousearth was washed with ethyl acetate, and the filtrate was concentratedin vacuo. The residue was then dissolved in toluene, and a catalyticamount of triethylamine was added. The reaction was refluxed for about 5days to form the lactam, with an additional 2-3 drops of triethylamineadded after the first day. The filtrate was then concentrated in vacuo.Ethyl acetate was added, and the mixture was washed with saturatedsodium bicarbonate solution, 2N HCl, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give 944 mg ofa yellow oil. Purification by silica gel chromatography on achromatotron using 75% ethyl acetate/hexanes as eluent afforded thetitle compound of part 7-G as a white foam (338 mg, 33%): +APcl MS(M+1)⁺ 331, (M−55)⁺ 275, (M−99)⁺ 231; ¹H NMR=400 MHz (CDCl₃) δ:7.26-7.10 (arom, m, 5H), 5.69 (NH, br s, 1H), 3.75 (—NHCH ₂—, br d, 2H),1.47 (BOC, s, 9H).

H.3a-Benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylicAcid tert-Butyl Ester

To the title compound of part 7-G (168 mg, 0.508 mmol) intetrahydrofuran (3 mL) under nitrogen atmosphere was added sodiumhydride (22 mg, 60% dispersion in oil, 0.55 mmol), and the mixture wasstirred for about 30 minutes at room temperature. Methyl iodide (0.315mL, 5.06 mmol) was added, and the reaction was stirred for about 3 hoursat room temperature. Additional methyl iodide (0.315 mL, 5.06 mmol) wasadded, and the reaction was stirred for about another 3 hours at roomtemperature. The reaction mixture was then concentrated in vacuo. Ethylacetate was added, and the mixture was washed with saturated sodiumthiosulfate solution, brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the title compound of part7-H as a colorless oil (187 mg, ca 100%): +APcl MS (M+1)⁺ 345, (M−55)⁺289; ¹H NMR=400 MHz (CDCl₃) δ: 7.25-7.15 (arom, m, 5H), 3.64 (—NMeCH ₂—,br, 2H), 2.70 (NMe, s, 3H), 1.47 (BOC, s, 9H).

I. 3a-Benzyl-2-methyl-octahydro-pyrrolo[3,4-c]pyridin-3-one,Hydrochloride

The title compound of part 7-H (185 mg, 0.537 mmol) in a solution of 4MHCl/dioxane (10 mL) was stirred at room temperature for about 4 hours.The reaction mixture was concentrated in vacuo to a gummy solid, whichwas triturated with ethyl ether to give a white solid. The ether wasdecanted off and the solid was dried in vacuo to give the title compoundof part 7-I (150 mg, 100%): +APcl MS (M+1)⁺ 245; ¹H NMR=400 MHz(methanol-d₄) δ: 7.29 (arom, m, 3H), 7.18 (arom, m, 2H), 2.70 (NMe, s,3H).

J.{1-[2-(3a-Benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

To a stirred solution of the title compound of part 2-I (190 mg, 0.500mmol), the title compound of part 7-I (150 mg, 0.534 mmol),1-hydroxy-7-azabenzotriazole (75 mg, 0.55 mmol), and NMM (118 μL, 1.05mmol) in dichloromethane at about 0° C. under nitrogen atmosphere wasslowly added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(106 mg, 0.55 mmol). The reaction was allowed to warm to roomtemperature overnight. The reaction was then concentrated in vacuo.Ethyl acetate was added, and the mixture was extracted with 2N HCl,saturated sodium bicarbonate solution, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give 257 mg ofa colorless oil. Purification by silica gel chromatography on achromatotron using 0-2% methanol/ethyl acetate as eluent afforded thetitle compound of part 7-J as a colorless oil (205 mg, 68%): +APcl MS(M+1)⁺ 607, (M−99)⁺ 507; ¹H NMR=400 MHz (methanol-d₄) δ: 7.30-7.02.(arom, m, 10H), 5.13 (NCHCO, br m, 1H), 4.50 (OCH ₂Ph, m, 2H), 1.43 (Me,m, 6H), 1.38 (BOC, m, 9H).

K.2-Amino-N-[2-(3a-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A solution of the title compound of part 7-J (195 mg, 0.321 mmol) in 4MHCl/dioxane (10 mL) was stirred at room temperature overnight. Thereaction was concentrated in vacuo to a gummy solid, which wastriturated with ethyl ether to give a solid. The solid was collected byfiltration to give the title compound of this Example 7 as a white solid(118 mg, 70%): +APcl MS (M+1)⁺ 507; ¹H NMR=400 MHz (methanol-d₄) δ:7.32-7.10 (arom, m, 10H), 5.12 (NCHCO, br m, 1H), 4.55 (OCHH₂Ph, m, 2H),1.60 (Me, m, 6H).

EXAMPLE 82-Amino-N-[2-(3a-benzyl-3-oxo-hexahydro-fluoro[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 3-Benzyl-4-methoxymethylene-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester

To a suspension of methoxymethyl triphenylphosphonium chloride (9.87 g,28.8 mmol) in anhydrous tetrahydrofuran (20 mL) was added a 1 M solutionof potassium tert-butoxide in tetrahydrofuran (31.7 mL, 31.7 mmol) atroom temperature for about 2 hours. The title compound of part 7-B (10g, 28.8 mmol) was then added, and the reaction was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, and washed twice with 10% aqueous HCl solution, saturatedsodium bicarbonate solution, brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to give crude product thetitle compound of part 8-A: +APcl MS (M−56)⁺ 319, (M−100)⁺ 275; ¹HNMR=300 MHz (CDCl₃) δ: 7.28-7.11 (arom, series of m, 5H), 6.61 (C═CH—,s, 1H), 3.60 (OMe, s, 3H), 3.55 (OMe, s, 3H), 1.40 (BOC, s, 9H).

B. 3-Benzyl-4-formyl-piperidine-1,3-dicarboxylic Acid 1-tert-Butyl Ester3-Methyl Ester

A solution of the title compound of part 8-A (430 mg, 1.15 mmol) andsodium iodide (343 mg, 2.29 mmol) in tetrahydrofuran (3 mL) was stirredat room temperature for about 2 days. The reaction mixture was dilutedwith ethyl acetate, and washed twice with saturated sodium bicarbonatesolution, brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to give the title compound of part 8-B as a yellowoil (410 mg, 99%): PB MS (M+1)⁺ 362, (M+18)⁺ 379, (M−55) 306, (M−99)262; ¹H NMR 250 MHz (CDCl₃) δ: 9.72 (aldehyde, d, 1H), 7.26-7.08 (arom,series of m, 5H), 3.60 (OMe, s, 3H), 1.48 (BOC, s, 9H).

C. 3a-Benzyl-3-oxo-hexahydro-furo[3,4-c]pyridine-5-carboxylic Acidtert-Butyl Ester

To a solution of the title compound of part 8-B (410 mg, 1.14 mmol) inmethanol (5 mL) at about 0° C. was added sodium borohydride (86 mg, 2.3mmol). The reaction was warmed to room temperature and stirred for about2.5 hours. The reaction mixture was cooled to about 0° C., and quenchedwith saturated ammonium chloride solution. The mixture was then dilutedwith ethyl acetate, and washed three times with saturated sodiumbicarbonate solution, twice with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to give crude product.Purification by silica gel chromatography using 20-60% ethylacetate/hexanes as eluent afforded the title compound of part 8-C (90mg, 24%): +APcl MS (M−55)⁺ 276, (M−99)⁺ 232; ¹H NMR=250 MHz (CDCl₃) δ:7.28-7.17 (arom, series of m, 5H), 1.50 (BOC, s, 9H).

D. 3a-Benzyl-hexahydro-furo[3,4-c]pyridin-3-one

The title compound of part 8-C (90 mg, 0.27 mmol) was deprotectedaccording to the method described in General Procedure C to give thecrude product as an HCl salt. This crude product was then diluted withchloroform, washed with saturated sodium bicarbonate solution, driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo togive crude product of the title compound of part 8-D as the free amine(50 mg, 81%): +APcl MS (M+1)⁺ 231; ¹H NMR=250 MHz (methanol-d₄) δ: 7.20(arom, m, 5H), 4.08 (CH ₂OCO—, m, 2H).

E.{1-[2-(3a-Benzyl-3-oxo-hexahydro-furo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure B, the title compound of part 8-D (50 mg,0.22 mmol) was coupled to the title compound of part 2-I (82 mg, 0.22mmol), and the product was purified by silica gel chromatography using50-80% ethyl acetate/hexanes as eluent to give the title compound ofpart 8-E (100 mg, 77%): PB MS (M+1)⁺ 594, (M+18)⁺ 611; ¹H NMR=250 MHz(CDCl₃) δ: 7.30-6.98 (arom series of m, 10H), 1.45 (Me, d, 6H), 1.40(BOC, s, 9H).

F.2-Amino-N-[2-(3a-benzyl-3-oxo-hexahydro-furo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The title compound of part 8-E (100 mg, 0.170 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of this Example 8 (50 mg, 55%): PB MS (M+1)⁺ 494; ¹HNMR=250 MHz (methanol-d₄) δ: 7.31-7.10 (arom, series of m, 10H), 1.57(Me, d, 6H).

EXAMPLE 92-Amino-N-[1(R)-benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamideHydrochloride

A. 4-Oxo-3-(R,S)-Pyridin-2-ylmethyl-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester

To a solution of 2.00 g (7.8 mmol) of3-benzyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-butyl ester, prepared analogously to the preparation of the methylester analog (the title compound of part 7-A), in 32 mL of THF was added468 mg (11.7 mmol) of sodium hydride (60% oil dispersion) at about 0° C.and the mixture was stirred for about 30 min. A solution of 762 mg (6.0mmol) 2-picolyl chloride in 5 mL of THF was added to the stirringsolution over about 5 min, followed by the addition of 432 mg (2.6 mmol)of potassium iodide. The ice bath was removed and the mixture was heatedfor about 17 h at reflux. The mixture was diluted with ethyl acetate andwashed once with water and once with brine, dried over MgSO₄, andconcentrated. The residue was purified by silica gel chromatographyusing (6:4 v/v ether:hexane) followed by (6:4 v/v ethyl acetate:hexane)to give 1.2 g of the title compound of part 9-A. MS (Cl, NH₃) 349 (MH⁺).

B. 4-Hydroxy-3-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Ethyl Ester

To a stirred solution of the title compound of part 9-A (8.0 g, 0.022mmol) in methanol (80 mL) at 0° C. was added sodium borohydride (0.836,0.022 mmol) portionwise. The reaction was stirred for about 3 hours atroom temperature. The reaction was quenched with saturated ammoniumchloride solution, the methanol was removed in vacuo, and the aqueousmixture was extracted several times with ethyl acetate. The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to give 10 g of crude product. Purification bysilica gel chromatography using 50-80% ethyl acetate/hexanes as eluentafforded the title compound of part 9-B (7.3 g, 91%): +APcl MS (M+1)⁺365, (M−55)⁺ 309, (M−99)⁺ 265; ¹H NMR=300 MHz (CDCl₃) δ: 8.48 (arom, d,1H), 7.67 (arom, t, 1H), 7.20 (arom, m, 1H), 7.00 (arom, br, 1H), 1.44(BOC, s, 9H), 1.20 (CH₂CH ₃, t, 3H).

C. 4-Hydroxy-3-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester

A solution of the title compound of part 9-B (2.3 g, 6.3 mmol) andaqueous 1 N NaOH (32 mL) in ethanol (30 mL) was stirred overnight atroom temperature. The reaction was then stirred overnight at about 35°C. The solvent was removed in vacuo, the aqueous mixture was dilutedwith water and dichloromethane, and then acidified to about pH 4.0-4.8with glacial acetic acid. The organic layer was removed, and the aqueouslayer was extracted several times with dichloromethane. All of theorganic layers were combined and dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to give the title compound of part9-C (2.2 g, 100%): −APcl MS (M−1)⁻ 335; ¹H NMR=300 MHz (methanol-d₄) δ:8.44 (arom, d, 1H), 7.75 (arom, t, 1H), 7.29 (arom, m, 2H), 1.40 (BOC,s, 9H).

D.2-Oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridine-5-carboxylicAcid tert-Butyl Ester

A solution of the title compound of part 9-C (2.2 g, 6.5 mmol),diphenylphosphoryl azide(1.8 g, 6.5 mmol), and triethylamine (661 mg,6.5 mmol) in benzene (25 mL) was heated to reflux for about 14 hours,then stirred at room temperature for about 2 days. The reaction was thenconcentrated in vacuo. Purification by silica gel chromatography usingethyl acetate/pentane as eluent afforded the title compound of part 9-D(492 mg, 22%): +APcl MS (M+1)⁺ 334, (M−55)⁺ 278; ¹H NMR=300 MHz (CDCl₃)δ: 8.50 (arom, d, 1H), 7.64 (arom, t, 1H), 7.16 (arom, m, 2H), 7.08 (NH,br s, 1H), 1.17 (BOC, s, 9H).

E.3-Methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridine-5-carboxylicAcid tert-Butyl Ester

To a stirred solution of the title compound of part 9-D (494 mg, 1.48mmol) in N,N-dimethylformamide was added sodium hydride (43 mg, 60%dispersion in mineral oil, 1.8 mmol) at room temperature. The mixturewas stirred for about 10 minutes, then methyl iodide (256 mg, 1.80 mmol)was added, and the reaction was stirred overnight. Water was added tothe reaction mixture, and the mixture was extracted several times withethyl acetate. The combined organic layers were then back-extractedseveral times with water. The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo to give 494 mg of crudeproduct. Purification by silica gel chromatography using 60% ethylacetate/hexanes as eluent afforded the title compound of part 9-E as acrystalline solid (273 mg, 53%): +APcl MS (M+1)⁺ 348, (M−55)⁺ 292,(M−99)⁺ 248; ¹H NMR=400 MHz (CDCl₃) δ: 8.51 (arom, br, 1H), 7.60 (arom,br, 1H), 7.18 (arom, br m, 2H), 2.85 (NMe, br, 3H), 1.46 (BOC, s, 9H).

F. 3-Methyl-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-2-oneDihydrochloride

To the title compound of part 9-E (270 mg, 0.778 mmol) in anhydrousdichloromethane (1 mL) was added a solution of 4M HCl/dioxane (1 mL, 4mmol), and the mixture was stirred for about 4 hours. The reactionmixture was then concentrated in vacuo to give the title compound ofpart 9-F (220 mg, 89%): +APcl MS (M+1)⁺ 248; ¹H NMR=300 MHz(methanol-d₄) δ: 8.78 (arom, d, 1H), 8.43 (arom, t, 1H), 8.00 (arom, d,1H), 7.91 (arom, t, 1H), 2.57 (NMe, s, 3H).

G.{1-[1(R)-Benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]1-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

To a stirred solution of the title compound of part 9-F (115 mg, 0.360mmol), the title compound of part 2-I (116 mg, 0.360 mmol),triethylamine (101 μL, 0.72 mmol), and 1-hydroxy-7-azabenzotriazole (61mg, 0.45 mmol) in dichloromethane (2 mL) cooled to about −30° C. wasadded 1,2-diethylaminoethyl chloride hydrochloride (69 mg, 0.36 mmol).The reaction was stirred at about −30° C. for about 2 hours, thenallowed to warm slowly to room temperature overnight. The reaction wasthen concentrated in vacuo. Purification by silica gel chromatographyusing ethyl acetate as eluent afforded the title compound of part 9-G(129 mg, 59%): +APcl MS (M+1)⁺ 610, (M−99)⁺ 510; ¹H NMR=300 MHz (CDCl₃)δ: 8.51 (arom, br d, 1H), 7.57 (arom, br, 1H), 7.25-7.15 (arom, m, 7H),1.42 (Me, s, 6H), 1.38 (BOC, br, 9H).

H.2-Amino-N-[1(R)-benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

To the title compound of part 9-G (125 mg, 0.205 mmol) in anhydrousdichloromethane (1 mL) was added 4M HCl/dioxane (1 mL), and the reactionwas stirred at room temperature overnight. The reaction was concentratedin vacuo to give the title compound of this Example 9 (133 mg, ca 100%):+APcl MS (M+1)⁺ 510; ¹H NMR=300 MHz (CDCl₃) δ: 8.80 (arom, m, 1H), 8.52(arom, m, 1H), 8.10 (arom, m, 1H), 8.02 (arom, m 1H), 7.35-7.27 (arom,series of m, 5H), 1.62 (Me, s, 3H), 1.59 (Me, s, 3H).

EXAMPLE 102-Amino-N-[2-(4a-benzyl-2-oxo-hexahydro-3-oxa-1,6-diaza-naphthalen-6-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 3-Benzyl-4-oxo-piperidine-3-carboxylic Acid Methyl Ester,Hydrochloride

To a stirred solution of the title compound of part 7-A (98.1 g, 282mmol) in ethyl ether/ethyl acetate (800 mL/200 mL) at room temperatureunder nitrogen atmosphere was bubbled in HCl gas for about 30 minutes.The reaction was stirred for about 1 hour, then HCl gas was bubbled infor about an additional 30 minutes and the reaction was stirred forabout another 1 hour. HCl gas was bubbled in for about an additional 1hour, and then the solid product was collected by filtration, rinsedwith ethyl ether, and dried in vacuo to give the title compound of part10-A as a white powder. (72 g, 90%); ¹H NMR=250 MHz (methanol-d₄) δ:7.29 (arom, m, 3H), 7.09 (arom, m, 2H), 3.81 (Me, s, 3H), 3.74-2.66(series of m, 8H).

B. 3-Benzyl-4-oxo-piperidine-3-carboxylic Acid Methyl Ester

The title compound of part 10-A was suspended in chloroform and washedtwice with saturated sodium bicarbonate solution, dried over sodiumsulfate, filtered and concentrated in vacuo to give a waxy solid. Thissolid was stirred in isopropyl ether (250 mL) overnight, and then thesolid product was collected by filtration and dried in vacuo to give thetitle compound of part 10-B as a white powder (23 g, 76%): TSMS (M+1)⁺248; ¹H NMR=250 MHz (methanol-d₄) δ: 7.22 (arom, m, 3H), 7.10 (arom, m,2H), 3.65 (Me, s, 3H), 3.54-2.35 (series of m, 8H).

C. 1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic Acid Methyl Ester

A solution of the title compound of part 10-B (17.0 g, 68.7 mmol),potassium carbonate (19.0 g, 138 mmol), and benzyl bromide (11.8 g, 68.7mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperatureovernight. The mixture was diluted with ethyl acetate and washed twicewith water, brine, dried over sodium sulfate and filtered. TheN,N-dimethylformamide was azeotroped off with heptane, and the productwas concentrated in vacuo to give the title compound of part 10-C as ayellow oil (19 g, 82%): PBMS (M+1)⁺ 338; ¹H NMR=250 MHz (CDCl₃) δ: 7.31(Ph, m, 5H), 7.21 (Ph, m, 5H), 3.64 (Me, s, 3H), 3.60 (s, 2H), 3.41-2.90(series of m, 8H).

D. 1,3-Dibenzyl-4-hydroxyimino-piperidine-3-carboxylic Acid Methyl Ester

To a stirred solution of the title compound of part 10-C (2.1 g, 6.2mmol) and triethylamine (0.90 mL, 6.2 mmol) in methanol (30 mL) wasadded hydroxylamine hydrochloride (433 mg, 6.22 mmol). The reaction wasstirred at room temperature for about 16 hours under nitrogenatmosphere. The reaction mixture was then concentrated in vacuo, dilutedwith dichloromethane, and then quenched with aqueous 10% HCl until themixture was at about pH 2. The organic layer was washed with saturatedsodium bicarbonate solution, brine, dried over sodium sulfate, filteredand concentrated in vacuo to give the title compound of part 10-D as ayellow, hygroscopic solid (1.7 g, 78%): +APcl MS (M+1)⁺ 353; ¹H NMR=300MHz (methanol-d₄) δ: 7.28-7.17 (arom, m, 10H), 5.47 (NOH, s, 1H), 3.52(Me, s, 3H), 3.48-2.20 (series of multiplets, 10H).

E. (4-Amino-1,3-dibenzyl-piperidin-3-yl)-methanol

To a stirred solution of the title compound of part 10-D (1.59 g, 4.51mmol) in tetrahydrofuran at about 0° C. under nitrogen atmosphere wasslowly added a 1M solution of lithium aluminum hydride (11.28 mL). Thereaction was slowly warmed to room temperature and then heated at refluxfor about 17 hours. The reaction was then cooled to about 0° C. andquenched with water (8 mL), then aqueous 15% NaOH (24 mL) was slowlyadded, followed by additional water (8 mL). The mixture was filtered,and the solid precipitate was rinsed with ethyl acetate (40 mL). Theorganic layer in the filtrate was separated and washed twice with brine,dried over sodium sulfate, filtered and concentrated in vacuo to givethe title compound of part 10-E as a yellow, hygroscopic solid (1.35 g,57%): +APcl MS (M+1)⁺ 311; ¹H NMR=250 MHz (methanol-d₄) δ: 7.18 (arom,m, 10H), 3.31-1.40 (series of m, 12H).

F. 4a,6-Dibenzyl-octahydro-3-oxa-1,6-diaza-naphthalen-2-one

A solution of the title compound of part 10-E (980 mg, 3.16 mmol),1,1′-carbonyldiimidazole (2.560 mg, 15.78 mmol), and triethylamine (0.90mL, 6.3 mmol) in ethylene glycol dimethyl ether was heated at reflux forabout 2 days under nitrogen atmosphere. The reaction was then cooled toroom temperature, and concentrated in vacuo. The mixture was dilutedwith chloroform (150 mL), and washed with water (30 mL) and then brine(30 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. Purification by silica gel chromatography using75% ethyl acetate/hexanes as eluent afforded the title compound of part10-F (410 mg, 39%): +APcl MS (M+1)⁺ 337; ¹H NMR=300 MHz (CDCl₃) δ:7.40-7.00 (arom, series of m, 10H), 6.34 (NH, br s, 1H), 3.75 (d of d,2H), 3.51 (s, 2H), 3.39 (m, 2H), 3.11 (br d, 1H), 2.68 (d of d, 2H),2.14-1.50 (series of m, 4H).

G. 4a-Benzyl-octahydro-3-oxa-1,6-diaza-naphthalen-2-one

The title compound of part 10-F (347 mg, 1.03 mmol), ethanol (50 mL),water (10 mL), and 10% palladium on carbon (347 mg) were combined andhydrogenated at 45 psi H₂ on a Parr® shaker overnight. The mixture wasthen filtered through a bed of diatomaceous earth. The diatomaceousearth was washed with ethanol (200 mL), and the filtrate wasconcentrated in vacuo. Purification by silica gel chromatography using75-100% ethyl acetate/hexanes as eluent afforded the title compound ofpart 10-G as a white solid (130 mg, 53%): +APcl MS (M+1)⁺ 247; ¹HNMR=250 MHz (methanol-d₄) δ: 7.29 (Ph, m, 5H), 3.78 (s, 1H), 3.35 (s,2H), 3.22-1.68 (series of m, 8H).

H.{1-[2-(4a-Benzyl-2-oxo-hexahydro-3-oxa-1,6-diaza-naphthalen-6-yl)-1-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

A solution of the title compound of part 10-G (125 mg, 0.507 mmol),1-hydroxy-7-azabenzotriazole (103 mg, 0.762 mmol), the title compound ofpart 2-I (290 mg, 0.762 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (107 mg, 0.558 mmol) inanhydrous dichloromethane (20 mL) was stirred at room temperatureovernight under nitrogen atmosphere. The reaction mixture was dilutedwith dichloromethane, and the solution was extracted with saturatedsodium bicarbonate solution and then brine. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo. Purification bysilica gel chromatography using 5% methanol/dichloromethane as eluentafforded the title compound of part 10-H as a white solid (93 mg, 30%):+APcl MS (M+1)⁺ 609, (M−99)⁺ 509; ¹H NMR=250 MHz (CDCl₃) δ: 7.25 (arom,m, 10H), 1.50-1.40 (Me, BOC, 15H).

I.2-Amino-N-[2-(4a-benzyl-2-oxo-hexahydro-3-oxa-1,6-diaza-naphthalen-6-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

To a stirred solution of the title compound of part 10-H (89 mg, 0.15mmol) in ethanol (30 mL) was added concentrated hydrochloric acid (8 mL)at room temperature. The reaction was stirred for about 30 minutes, thenconcentrated in vacuo. The residue was dissolved in methanol (1 mL),ethyl acetate was added, and the product precipitated out as a solid.The solvent was removed in vacuo to give the title compound of thisExample 10 as a white solid (83 mg, 100%): +APcl MS (M+1)⁺ 509; ¹HNMR=250 MHz (methanol-d₄) δ: 7.20 (arom, m, 10H), 1.58 (Me, br s, 3H)1.50 (Me, br s, 3H).

EXAMPLE 112-Amino-N-[2-(3a-benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 2-Methyl-pyrrolo[3,4-c]pyridine-1,3-dione

To a stirred solution of 3,4-pyridinedicarboximide (10.0 g, 67.5 mmol)in N,N-dimethylformamide was added sodium hydride (1.55 g, 60%dispersion in mineral oil, 67.5 mmol) at room temperature. The mixturewas stirred for about 30 minutes, then methyl iodide (9.58 g, 67.5 mmol)was added, and the reaction was stirred overnight. Ethyl acetate wasadded to the reaction mixture, and the mixture was extracted once withwater, twice with brine. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo (azeotropingexcess N,N-dimethylformamide with heptanes) to give crude product.Purification by silica gel chromatography using 0-5%methanol/dichloromethane as eluent afforded the title compound of part11-A as an off-white solid (5 g, 46%): PB MS (M+1)⁺ 163; ¹H NMR=250 MHz(CDCl₃) δ: 9.11 (arom, s, 1H), 9.08 (arom, d, 1H), 7.75 (arom, d, 1H),3.20 (Me, s, 3H).

B. 2-Methyl-hexahydro-pyrrolo[3,4-c]pyridine-1,3-dione, Hydrochloride

The title compound of part 11-A (1.00 g, 6.17 mmol), ethanol (20 mL), 3NHCl (5 mL), and 10% palladium on carbon (1.0 g) were combined andhydrogenated at about 45 psi H₂ on a Parr shaker overnight. The mixturewas then filtered through a bed of diatomaceous earth. The diatomaceousearth was washed with ethanol, and the filtrate was concentrated invacuo to give the title compound of part 11-B as a white solid (1.35 g,100%): PB MS (M+1)⁺ 169; ¹H NMR=300 MHz (methanol-d₄) δ: 2.98 (Me, s,3H).

C. 2-Methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic Acidtert-Butyl Ester

To a stirred solution of the title compound of part 11-B (1.27 g, 6.20mmol) and 4-dimethylaminopyridine (1.51 g, 12.4 mmol) in dichloromethane(100 mL) cooled to about 0° C. was added a solution of di-tert-butyldicarbonate (1.35 g, 6.20 mmol) in dichloromethane dropwise. Thereaction was then allowed to warm slowly to room temperature overnight.The reaction was concentrated in vacuo. Ethyl acetate was added to thereaction mixture, and the mixture was extracted twice with 10% HCl,twice saturated sodium bicarbonate solution, and twice with brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give the title compound of part 11-C as a lightyellow oil (1.2 g, 72%): PB MS (M+1)⁺ 269, (M+18)⁺ 286; ¹H NMR=300 MHz(CDCl₃) δ: 2.85 (Me, s, 3H), 1.34 (BOC, s, 9H).

D.3a-Benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylicAcid tert-Butyl Ester

To a stirred solution of the title compound of part 11-C (600 mg, 2.24mmol) in tetrahydrofuran (10 mL) cooled to about −78° C. was added a 1Msolution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.33mL) was slowly added over about 10 minutes. The reaction was stirred atabout −78° C. for about 30 minutes, and then benzyl bromide (0.28 mL,2.3 mmol) was added. The reaction was allowed to slowly warm to roomtemperature and was stirred for about 3 days. The reaction wasconcentrated in vacuo, and water was added. The mixture was extractedtwice with ethyl acetate. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to givecrude product. Purification by silica gel chromatography using 15-100%ethyl acetate/hexanes as eluent afforded the title compound of part 11-D(470 mg, 59%): PB MS (M+1)⁺ 359, (M+18)⁺ 376; ¹H NMR=300 MHz (CDCl₃) δ:7.20 (arom., m, 3H), 7.06 (arom., m, 2H), 2.80 (Me, s, 3H), 1.40 (BOC,s, 9H).

E. 3a-Benzyl-2-methyl-hexahydro-pyrrolo[3,4-c]pyridine-1,3-dione,Hydrochloride

The title compound of part 11-D (450 mg, 1.26 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of part 11-E (370 mg, 99%): PB MS (M+1)⁺ 259; ¹H NMR=250MHz (methanol-d₄) δ: 7.28 (arom., m, 3H), 7.14 (arom., m, 2H), 2.70 (Me,s, 3H).

F.{1-[2-(3a-Benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-Butyl Ester

According to General Procedure B, the title compound of part 11-E (150mg, 0.51 mmol) was coupled to the title compound of part 2-I (193 mg,0.51 mmol), and the product was purified by silica gel chromatographyusing 50-100% ethyl acetate/hexanes as eluent to give the title compoundof part 11-F (180 mg, 57%): PB MS (M+1)⁺ 621, (M+18)⁺ 638; ¹H NMR=250MHz (CDCl₃) δ: 7.30-6.90 (arom., series of m, 10H), 1.44 (Me, s, 6H),1.40 (BOC, s, 9H).

G.2-Amino-N-[2-(3a-benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The title compound of part 11-F (180 mg, 0.29 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of this Example 11 (120 mg, 74%): PB MS (M+1)⁺ 521; ¹HNMR=300 MHz (methanol-d₄) δ: 7.30-7.10 (arom., series of m, 10H), 1.55(Me, br s, 6H).

EXAMPLE 122-Amino-N-[1(R)-benzyloxymethyl-2-(2-ethyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

A. 2-Ethyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4one

7-Benzyl-2-ethyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (270mg, 1.00 mmol), prepared by the method of Lazar et al. (J. Heterocycl.Chem. 1990, 27, 1885), was de-benzylated according to the methoddescribed in General Procedure D to give the title compound of part 12-Aas a white powder (160 mg, 89%): PB MS (M+1)⁺ 180; ¹H NMR=300 MHz(methanol-d₄) δ: 3.70 (—NCH ₂—, s, 2H), 3.20 (—NCH ₂—, t, 2H), 2.58 (CH₂Me, t, 2H), 2.48 (—CH ₂—C—CO, br t, 2H), 1.25 (Me, t, 3H).

B.{1-[1-Benzyloxmethyl-2-(2-ethyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure B, the title compound of part 12-A (80mg, 0.45 mmol) was coupled to the title compound of part 2-I (170 mg,0.450 mmol), and the product was purified by silica gel chromatographyusing 0-8% methanol/dichloromethane as eluent to give the title compoundof part 12-B (160 mg, 66%): PB MS (M+1)⁺ 542, (M−99)⁺ 442; ¹H NMR=250MHz (CDCl₃) δ: 7.21 (arom., m, 5H), 1.50 (Me, d, 6H), 1.40 (BOC, d, 9H),1.25 (—CH₂CH ₃, d of t, 3H).

C.2-Amino-N-[1(R)-benzyloxymethyl-2-(2-ethyl-4-oxo-4,5,6,8-tetrahydro-3H-Pyrido[3,4-d]pyrimidin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The title compound of part 12-B (160 mg, 0.300 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of this Example 12 as an off-white powder (100 mg, 70%):PB MS (M+1)⁺ 442; ¹H NMR=250 MHz (methanol-d₄) δ: 7.30 (arom., m, 5H),1.58 (Me, s, 6H), 1.40 (CH₂CH ₃, t, 3H).

EXAMPLE 132-Amino-N-[1(R)-benzyloxymethyl-2-(2-ethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 6-Benzyl-2-ethyl-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

To a stirred solution of 1-benzyl-3-carboethoxy-4-piperidonehydrochloride (10 g, 34 mmol), prepared by the method of Lazar et al.(J. Heterocycl. Chem. 1990, 27, 1885), in ethanol (200 mL) was addedpropylamidine hydrochloride (4.01 mg, 36.9 mmol), followed by sodiumhydride (2.32 mg, 60% dispersion in mineral oil, 101 mmol). The reactionwas heated to about 100° C. and stirred for about 2 days, then cooled toroom temperature and stirred for about 1 day. The reaction wasconcentrated in vacuo, and ethyl acetate was added. The mixture wasextracted once with water, twice with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give crudeproduct. Purification by silica gel chromatography using 2-10%methanol/dichloromethane as eluent afforded the title compound of part13-A (1.9 g, 21%): PB MS (M+1)⁺ 270; ¹H NMR=250 MHz (methanol-d₄) δ:7.32 (arom., m, 5H), 2.60 (CH ₂CH₃, q, 2H), 1.28 (CH₂CH ₃, t, 3H).

B. 2-Ethyl-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The title compound of part 13-A (1.0 g, 3.7 mmol) was de-benzylatedaccording to the method described in General Procedure D to give thetitle compound of part 13-B (640 mg, 97%): PB MS (M+1)⁺ 180; ¹H NMR=300MHz (methanol-d₄) δ: 2.60 (CH ₂CH₃, q, 2H), 1.28 (CH₂CH ₃, t, 3H).

C.{1-[1-Benzyloxymethyl-2-(2-ethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

According to General Procedure B, the title compound of part 13-B (140mg, 0.78 mmol) was coupled to the title compound of part 2-I (298 mg,0.78 mmol), and the product was purified by silica gel chromatographyusing 2-10% methanol/dichloromethane as eluent to give the titlecompound of part 13-C (270 mg, 64%): PB MS (M+1)⁺ 542, (M−99)⁺ 442; ¹HNMR=300 MHz (methanol-d₄) δ: 7.20 (arom., m, 5H), 1.38 (BOC, s, 9H),1.31 (Me, s, 6H), 1.27 (—CH₂CH ₃, m, 3H).

D.2-Amino-N-[1(R)-benzyloxymethyl-2-(2-ethyl-4-oxo-3,5,7,8tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The title compound of part 13-C (250 mg, 0.46 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of this Example 13 (200 mg, 91%): PB MS (M+1)⁺ 442; ¹HNMR=250 MHz (methanol-d₄) δ: 7.28 (arom., m, 5H), 1.60 (Me, s, 6H), 1.40(CH₂CH ₃, t, 3H).

The following abbreviations and notations are used in the Tables below.Abbreviation:

Me—methyl

Et—ethyl

Ph—phenyl

Pyr—pyridyl

A=Mass Spec. Method is ⁻AP_(c)l

B=Mass Spec. Method is PB

C=Mass Spec. Method is ⁺AP_(c)l

EXAMPLES 14-58

The compounds of examples 14-58 were synthesized in a manner analogousto the procedures described for Examples 3, 3a, 4 and 5, using theappropriate starting materials.

Ex. # R² R¹ R″ isomer MS 14 Me CH₂Ph OCH₂Ph d2 523^(C) 15 Me CH₂PhOCH₂Ph d1 522^(B) 16 Me CH₂-4-F—Ph OCH₂Ph d2 540^(C) 17 Me CH₂-4-F—PhOCH₂Ph d1 523^(C) 18 Me CH₂Ph OCH₂-2-Pyr d1,2 523^(B) 19 Me CH₂-3-PyrOCH₂Ph d1,2 523^(B) 20 Me CH₂Ph OCH₂-3-Pyr d1,2 523^(C) 21 Me CH₂-2-PyrOCH₂Ph d1,2 523^(C) 22 Me CH₂Ph 2-Indole d1,2 531^(C) 23 Me CH₂PhOCH₂-4-Thiazole d1,2 529^(C) 24 Et CH₂Ph OCH₂-3,4-di-F—Ph d1,2 572^(C)25 Me CH₂Ph OCH₂-2,4- d2 658^(C) di(CF₃)Ph 26 CF₃CH₂ CH₂-4-CF₃—Ph OCH₂Phd1,2 657^(C) 27 CF₃CH₂ CH₂-4-CF₃—Ph 2-Indole d1,2 667^(C) 28 CF₃CH₂CH₂-4-F—Ph OCH₂Ph d1,2 608^(C) 29 CF₃CH₂ CH₂-4-F—Ph OCH₂-2,4-di-F—Phd1,2 644^(C) 30 Me CH₂-4-F—Ph 3-Indole d1,2 549^(C) 31 Me CH₂-4-F—PhOCH₂-2,4-di-F—Ph d1,2 576^(C) 32 Me H 3-Indole d1,2 441^(C) 33 CF₃CH₂ HOCH₂-2,4-di-F—Ph d1,2 468^(C) 34 Me H OCH₂-2,4-di-F—Ph d1,2 536^(C) 35CF₃CH₂ CH₂-3,4-di-F—Ph 3-Indole d1,2 635^(C) 36 CF₃CH₂ CH₂-3,4-di-F—PhOCH₂Ph d1,2 626^(C) 37 CF₃CH₂ CH₂-3,4-di-F—Ph OCH₂-2,4-di-F—Ph d1,2662^(C) 38 Me CH₂Ph OCH₂-3,4-di-F—Ph d2 558^(C) 39 CF₃CH₂ CH₂-3-F—Ph3-Indole d2 617^(C) 40 CF₃CH₂ CH₂-3-F—Ph 3-Indole d1 617^(C) 41 CF₃CH₂—CH₂-2-F—Ph OCH₂Ph d1,2 591^(C) 42 Me CH₂-2-Pyr OCH₂Ph d2 523^(C) 43 MeH OCH₂Ph d1,2 432^(C) 44 CF₃CH₂ CH₂Ph OCH₂Ph d2 590^(C) 45 CF₃CH₂ CH₂PhOCH₂Ph d1 590^(C) 46 CF₃CH₂ CH₂-2-Pyr OCH₂Ph d1 591^(C) 47 CF₃CH₂CH₂-2-Pyr OCH₂Ph d2 591^(C) 48 CF₃CH₂ CH₂-3-Pyr OCH₂-2,4-di-F—Ph d1,2627^(C) 49 CF₃CH₂ CH₂-3-Pyr OCH₂-2-CF₃—Ph d1,2 659^(C) 50 CF₃CH₂CH₂-3-Pyr OCH₂-4-Cl—Ph d1,2 625^(C) 51 CF₃CH₂ CH₂-3-Pyr OCH₂-2-Pyr d1,2592^(C) 52 CF₃CH₂ CH₂-3-Pyr OCH₂-4-F—Ph d1,2 609^(C) 53 CF₃CH₂ CH₂-3-PyrOCH₂-2,3-di-F—Ph d1,2 626^(C) 54 CF₃CH₂ CH₂-3-Pyr OCH₂-3-Pyr d1,2592^(C) 55 CF₃CH₂ CH₂-2-Pyr OCH₂-2,4-di-F—Ph d2 627^(C) 56 CF₃CH₂CH₂-2-Pyr OCH₂-2-CF₃—Ph d2 659^(C) 57 CF₃CH₂ CH₂-2-Pyr OCH₂-2-Pyr d2592^(C) 58 CF₃CH₂ CH₂-2-Pyr OCH₂-4-Cl—Ph d2 625^(C)

EXAMPLES 59-60

The compounds of examples 59-60 were synthesized in a manner analogousto the procedures described for Examples 3, 3a, 4 and 5, using theappropriate starting materials.

Ex. # R² R¹ R″ MS 59 Me CH₂-4-F—Ph 1-Naphthalene 586^(C) 60 CF₃CH₂CH₂-3,4-di-F—Ph 1-Naphthalene 672^(C)

EXAMPLES 61-63

The compounds of examples 61-63 were synthesized in a manner analogousto the procedures described for Example 2, using the appropriatestarting materials.

CP# R″ isomer MS 61 OCH₂Ph d2 508^(C) 62 OCH₂Ph d1 508^(C) 63 3-Indoled1,2 517^(C)

EXAMPLES 64-95

The compounds of examples 64-95 were synthesized in a manner to theprocedures described for Example 1, using the appropriate startingmaterials.

Ex. # R¹ R″ isomer MS 64 CH₂Ph OCH₂Ph d2 495^(C) 65 CH₂Ph OCH₂Ph d1495^(C) 66 CH₂-2-Pyr OCH₂Ph d1,2 495^(C) 67 CH₂-4-Thiazole OCH₂Ph d1,2501^(C) 68 CH₂-5-Thiazole OCH₂Ph d1,2 502^(C) 69 CH₂Ph OCH₂-2-Pyr d2496^(C) 70 CH₂Ph OCH₂-2-Pyr d1 496^(C) 71 CH₂-4-Pyr OCH₂Ph d1,2 496^(C)72 CH₂Ph OCH₂-4-Pyr d1,2 496^(C) 73 CH₂Ph OCH₂-2-(Me)Ph d2 509^(C) 74CH₂Ph OCH₂-2-(Me)Ph d1 509^(C) 75 CH₂Ph OCH₂-2,4-di-F—Ph d2 531^(C) 76CH₂Ph OCH₂-2,4-di-F—Ph d1 531^(C) 77 CH₂Ph OCH₂-3-Pyr d1,2 496^(C) 78CH₂Ph OCH₂-3-(Me)Ph d2 509^(C) 79 CH₂Ph OCH₂-3-(Me)Ph d1 509^(C) 80CH₂-3-Pyr OCH₂Ph d1,2 496^(C) 81 CH₂Ph 3-Indole d1,2 504^(C) 82 CH₂PhOCH₂-4-Thiazole d1,2 502^(C) 83 CH₂-4-(CF₃)—Ph 3-Indole d1,2 572^(C) 84CH₂-4-(CF₃)—Ph OCH₂Ph d1,2 563^(C) 85 CH₂Ph OCH₂-3,5-di(CF₃)—Ph d2631^(C) 86 CH₂Ph OCH₂-3,5-di(CF₃)—Ph d1 631^(C) 87 CH₂PhOCH₂-3,5-di-Cl—Ph d2 563^(C) 88 CH₂Ph OCH₂-3,5-di-Cl—Ph d1 559^(C) 89CH₂-4-F—Ph 3-Indole d1,2 522^(C) 90 CH₂-4-F—Ph OCH₂Ph d1,2 513^(C) 91CH₂-3,4-di-F—Ph OCH₂-2,4-di-F—Ph d1,2 567^(C) 92 CH₂-3,4-di-F—Ph OCH₂Phd1,2 531^(C) 93 CH₂-3,5-di(CF₃)—Ph 3-Indole d1,2 640^(C) 94CH₂-3,5-di(CF₃)—Ph OCH₂Ph d1,2 641^(C) 95 CH₂-3,5-di(CF₃)—PhOCH₂-2,4-di-F—Ph d1,2 667^(C)

EXAMPLES 96-97

The compounds of examples 96-97 were synthesized in a manner analogousto the procedures described for Example 1, using the appropriatestarting materials.

Ex. # R¹ R″ MS 96 CH₂-4-(CF₃)Ph 1-Naphthalene 609^(C) 97 CH₂-4-F—Ph1-Naphthalene 559^(C)

EXAMPLES 98-150

The compounds of examples 98-150 were synthesized in a manner analogousto the procedures described for Example 9, using the appropriatestarting materials.

Ex. # R² R¹ R″ isomer MS  98 H CH₂Ph OCH₂Ph d2 510   99 H CH₂Ph OCH₂Phd1 495  100 H CH₂Ph OCH₂Ph d3 495  101 H CH₂Ph 3-Indole d1 504^(C) 102Me CH₂Ph 3-Indole d1 518^(C) 103 H CH₂Ph 3-Indole d3 503^(C) 104 MeCH₂Ph 3-Indole d3 517^(C) 105 H H OCH₂Ph d1,2 405^(C) 106 H CH₂Ph3-(N-Me)Indole d2 518^(C) 107 H CH₂Ph OCH₂-2-Pyr d2 496^(C) 108 H CH₂Ph5-Thiazole d3 502^(C) 109 H CH₂Ph SCH₂Ph d3 511^(C) 110 H CH₂-4-PyrOCH₂Ph d1,2,3,4 496^(C) 111 H CH₂Ph SCH₂Ph d2 511^(C) 112 Me CH₂-4-PyrOCH₂Ph d1 510^(B) 113 Me CH₂-4-Pyr OCH₂Ph d2 510^(B) 114 H CH₂-3-PyrOCH₂Ph d1,2 496^(B) 115 H CH₂-3-Pyr OCH₂Ph d3,4 496^(B) 116 H CH₂-2-PyrOCH₂Ph d2 496^(C) 117 H CH₂-2-Pyr OCH₂Ph d3 496^(C) 118 Me CH₂-4-PyrOCH₂Ph d3 510^(B) 119 Me CH₂-4-Pyr OCH₂Ph d4 510^(B) 120 Me CH₂-4-PyrOCH₂-2-Pyr d1,2,3,4 511^(B) 121 Me CH₂-3-Pyr OCH₂Ph d1,2,3,4 510^(B) 122Me CH₂-3-Pyr OCH₂Ph d1,2,3,4 510^(B) 123 Me CH₂-3-Pyr OCH₂Ph d1,2,3,4510^(B) 124 Me CH₂-4-Pyr 3-Indole d1,2,3,4 519^(B) 125 H CH₂-4-Pyr3-Indole d1,2,3,4 505^(B) 126 H CH₂-5- OCH₂Ph d1,2,3,4 502^(B) Thiazole127 H CH₂CH₂Ph OCH₂Ph d1,2,3,4 523^(B) 128 Me CH₂CH₂Ph OCH₂Ph d1,2,3,4537^(B) 129 Me CH₂-3-Pyr OCH₂-2-CF₃—Ph d1,2 578^(B) 130 Me CH₂-3-PyrOCH₂-2-CF₃—Ph d3 578^(B) 131 Me CH₂-3-Pyr OCH₂-2-CF₃—Ph d4 578^(B) 132Me CH₂-2-Pyr OCH₂Ph d2 510^(C) 133 Me CH₂-2-Pyr OCH₂-2,4-di-F—Ph d2546^(C) 134 H CH₂-3-Pyr OCH₂-2,4-di-F—Ph d1,2 532^(C) 135 Me CH₂-3-PyrOCH₂-2,4-di-F—Ph d1,2 546^(C) 136 Me CH₂-3-Pyr OCH₂-4-Cl—Ph d1,2 544^(C)137 Et CH₂-3-Pyr OCH₂Ph d1,2 524^(C) 138 Et CH₂-3-Pyr OCH₂-2,4-di-F—Phd1,2 560^(C) 139 Et CH₂-3-Pyr OCH₂-4-Cl—Ph d1,2 558^(C) 140 CH₂Ph HOCH₂Ph d1,2 495^(C) 141 CH₂Ph H OCH₂-2-Pyr d1,2 496^(C) 142 CH₂-2-Pyr HOCH₂Ph d2 496^(C) 143 CH₂-2-Pyr H OCH₂Ph d1 496^(C) 144 CH₂-2-Pyr HOCH₂-2,4-di-F—Ph d2 532^(C) 145 CH₂-2-Pyr H OCH₂-2,4-di-F—Ph d1 532^(C)146 CH₂-2-Pyr H OCH₂-2-CF₃—Ph d2 564^(C) 147 CH₂-2-Pyr H OCH₂-2-CF₃—Phd1 564^(C) 148 H CH₂-3,5-di-Cl- OCH₂—Ph d1,2 564^(C) 4-Pyr 149 HCH₂-3,5-di-Cl- OCH₂—Ph d3,4 564^(C) 4-Pyr 150 CH₂-2-Pyr H OCH₂-2-Pyrd1,2 497^(C)

EXAMPLES 151-163

The compounds of examples 151-163 were synthesized in a manner analogousto the procedures described for Example 11, using the appropriatestarting materials.

Ex. # R² R¹ R″ MS 152 Me H OCH₂Ph 431^(B) 153 Me H 3-Indole 440^(B) 154H H 3-Indole 426^(B) 155 Me CH₂Ph OCH₂Ph 521^(B) 156 Me CH₂Ph 2-Indole530^(B) 157 Me CH₂Ph OCH₂-2-Pyr 522^(B) 158 Me CH₂-2-Pyr OCH₂Ph 522^(B)159 Me CH₂Ph OCH₂-2,4-di-F—Ph 557^(B) 160 Me CH₂-2-Pyr OCH₂-2,4-di-F—Ph558^(B) 161 Me CH₂Ph OCH₂-4-Thiazole 528^(B) 162 Me CH₂PhOCH₂-4-Thiazole 528^(B) 163 Me CH₂-2-Pyr OCH₂-2-(Me)Ph 536^(B)

EXAMPLES 164-171

The compounds of examples 164-171 were synthesized in a manner analogousto the procedures described for Example 13, using the appropriatestarting materials.

Ex # R¹ R² R″ MS 164 Ph H OCH₂Ph 490^(B) 165 Et H OCH₂Ph 442^(B) 166 MeMe OCH₂Ph 442^(B) 167 Me Me 3-Indole 451^(B) 168 Et Me OCH₂Ph 456^(B)169 Et Me 3-Indole 465^(B) 170 Et CH₂Ph OCH₂Ph 532^(B) 171 Et CH₂Ph3-Indole 541^(C)

EXAMPLES 172-176

The compounds of examples 172-176 were synthesized in a manner analogousto the procedures described for Example 7, using the appropriatestarting materials.

Ex. # R² R¹ R″ MS 172 Me CH₂Ph OCH₂Ph 507^(C) 173 H CH₂Ph OCH₂Ph 493^(C)174 H CH₂Ph OCH₂-3-Pyr 494^(B) 175 H CH₂Ph OCH₂-2-Pyr 494^(B) 176 HCH₂Ph CH₂CH₂Ph 491^(C)

EXAMPLES 177-178

The compounds of examples 177-178 were synthesized in a manner analogousto the procedures described for Example 8, using the appropriatestarting materials.

Ex. # R¹ R″ MS 177 CH₂Ph OCH₂Ph 494^(B) 178 CH₂Ph OCH₂-2-Pyr 495^(C)

EXAMPLE 179-187

The compounds of examples 179-187 were synthesized in a manner analogousto the procedures described for Example 6, using the appropriatestarting materials.

Ex. # R¹ X R″ isomer MS 179 CH₂-2-F—Ph O OCH₂Ph d2 525^(C) 180CH₂-2-F—Ph O OCH₂Ph d1 525^(C) 181 CH₂-4-F—Ph O OCH₂Ph d2 525^(C) 182CH₂-4-F—Ph O OCH₂Ph d1 525^(C) 183 CH₂-4-F—Ph O OCH₂-2,4-di-F—Ph d2561^(C) 184 CH₂-4-F—Ph O OCH₂-2,4-di-F—Ph d1 561^(C) 185 CH₂-4-F—Ph SOCH₂Ph d1, 2 541^(C) 186 CH₂-2-Pyr O OCH₂-2,4-di-F—Ph d1, 2 544^(C) 187CH₂-2-Pyr O OCH₂Ph d1, 2 508^(C)

EXAMPLES 188-196

The compounds of examples 188-196 were synthesized by coupling the HETportion to the dipeptidyl portion in a manner analogous to theprocedures described in General Procedure B or Example part 3a-B; theHET portion was synthesized in a manner analogous to the methodindicated, using the appropriate materials.

Method of Preparation Ex. # HET R″ of HET MS 188

3-Indole Scheme 57 474 (TSMS) 189

3-Indole Scheme 57 460^(B) 190

OCH₂Ph Scheme 35 521^(B) 191

OCH₂-2-Pyr Example 12 471^(B) 192

OCH₂Ph Scheme 58 529^(B) 193

OCH₂Ph Scheme 27 557^(C) 194

3-Indole Scheme 27 530^(C) 195

OCH₂Ph Scheme 56 525^(C) 196

OCH₂Ph Scheme 56 525^(C)

EXAMPLE 1972-Amino-N-[1(R)-benzyloxymethyl-2-oxo-2-(3-oxo-8a(R,S)-pyridin-2-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide,Hydrochloride

A. 2-Formyl-2-pyridin-2-ylmethyl-piperazine-1,4-dicarboxylic Acid1-Benzyl Ester 4tert-Butyl Ester

A solution of the ester of Example 3, Step A (1.4 g, 3 mmol) in CH₂Cl₂(10 mL) was cooled to −50° C. and a 1.0 M solution of DIBAL in CH₂Cl₂(18 mL 18 mmol) was slowly added. Once the DIBAL addition was completethe solution was stirred at −50° C. for 1 h. The reaction was quenchedwith MEOH (2 mL) and 1 N NaOH (25 mL) was added. The aldehyde wasextracted with CH₂Cl₂ (3×25 mL). The extracts were combined, washed withbrine, dried over MgSO₄ and concentrated to give the aldehyde of Example197, Step A as a yellow oil (1.0 g, 76%) which was carried on withoutfurther purification: +APcl MS (M+1)⁺ 440, (M−^(t)Bu+1)⁺ 384, (M−Boc+1)⁺340; ¹H NMR=400 MHz (CDCl₃) δ: 9.51 (br s, 1H), 4.55 (m, 2H), 1.38 (s,9H).

B.2-(Hydroxyimino-methyl)-2-pyridin-2-ylmethyl-piperazine-1,4-dicarboxylicAcid 1-Benzyl Ester 4-tert-Butyl Ester

A solution of the aldehyde of Example 197, Step A (439 mg, 1 mmol) andhydroxylamine hydrochloride (278 mg, 4 mmol) in pyridine (5 mL) wasstirred for 12 h at rt. Solvent was removed under reduced pressure andthe resulting residue was dissolved into chloroform (20 mL), washed withsaturated NaHCO₃ and brine solutions, dried over MgSO₄ and concentratedto give 462 mg of a crude yellow oil. Purification by flashchromatography (SiO₂ gel, 3:1 EtOAc:hexane) delivered 342 mg (75%) ofthe oxime of Example 197, Step B as a colorless oil: +APcl MS (M+1)⁺455, (M−Bu+1)⁺ 399, (M−Boc+1)⁺ 355; ¹H NMR=400 MHz (CDCl₃) δ: 8.55 (m,1H), 5.27 (m, 1H), 4.98 (m, 1H), 1.42 (s, 9H).

C.3-Oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicAcid tert-Butyl Ester

To a solution of the oxime of Example 197, Step B (342 mg, 0.75 mmol) inEtOH (10 mL) was added Raney nickel (1 mL of a suspension in water),followed by NaOH (150 mg, 3.75 mmol). The mixture was stirred at roomtemperature for 2 h and filtered through Celite®. The filtrate wasconcentrated to afford the urea of Example 197, Step C as a white solid(534 mg, quantitative crude) which was carried on without furtherpurification: +APcl MS (M+1)⁺ 333, (M−^(t)Bu+1)⁺ 277, (M−Boc+1)⁺ 233.

D.{1-[1(R)-Benzyloxymethyl-2-oxo-2-(3-oxo-8a(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

To a solution of the crude urea of Example 197, Step C (534 mg) in EtOH(15 mL, 0° C.) was added conc. HCl (1.5 mL). The solution was stirred at0° C. for 1 h and concentrated down to provide the deprotectedpiperazine as a viscous, colorless oil: +Apcl MS (M+1)⁺ 333.

The residue was dissolved into 15 mL EtOAc and triethylamine (0.2 mL,1.5 mmol) was added. After stirring for 15 min, the acid of Example 2,Step 1 (380 mg, 1 mmol), PPAA (0.32 mL, 1 mmol) and triethylamine (0.4mL, 4 mmol) were added and the mixture was stirred at room temperaturefor 4 h. Water (20 ml) was added and the product was extracted withEtOAc (3×25 mL). The combined extracts were washed with brine, driedover MgSO4 and concentrated to give 612 mg of a crude yellow oil.Purification by flash chromatography (SiO₂ gel, 9:1 EtOAc:EtOH)delivered 72 mg (16% yield from the oxime) of the compound of Example197, Step D as a 1:1 mixture of diastereomers: +APcl MS (M+1)⁺ 595,(M−Boc+1)⁺ 495; ¹H NMR=400 MHz (CDCl₃) δ: 8.47 (br m, 1H), 5.18 (br m,1H), 4.85 (br, m, 1H), 1.45 (s, 0.5×3H), 1.44 (s, 0.5×3H), 1.42 (br s,3H) 1.39 (br s, 9H).

E.2-Amino-N-[1(R)-benzyloxymethyl-2-oxo-2-(3-oxo-8a(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-ethyl-2-methyl-propionamide,Hydrochloride

To a solution of the compound of Example 197, Step D (30 mg) in EtOH (5mL), at 0° C. was added conc. HCl (0.5 mL). The solution was stirred at0° C. for 1 h and concentrated down to deliver 28 mg of the compound ofExample 197, Step E: +APcl MS (M+1)⁺ 495; ¹H NMR=400 MHz (CD₃OD) δ; 8.58(br m, 1 H), 4.58 (br m, 2H), 1.61 (br s, 6H).

EXAMPLE 1982-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(2,4-difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

A. 3-(2,4-Difluoro-benzyl)-3-formyl-piperazine-1-carboxylic Acidtert-Butyl Ester

A solution of ester 3-(2,4-difluoro-benzyl)-piperazine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester, prepared analogously to thecompound of Example 2, Step A, (1.11 g, 3 mmol) in CH₂Cl₂ (10 mL) wascooled to −40° C. and a 1.0 M solution of DIBAL in CH₂Cl₂ (9 mL, 9 mmol)was slowly added. Once the DIBAL addition was complete the solution wasallowed to stir at −40° C. for 1 h. The reaction was quenched with MeOH(2 mL) and 1 N NaOH (25 mL) was added. The aldehyde was extracted withCH₂Cl₂(3×20 mL). The extracts were combined, washed with brine, driedover MgSO₄ and concentrated to give the compound of Example 198, Step Aas a yellow oil (647 mg, 64%) which was carried on without furtherpurification: +APcl MS (M+1)⁺ 341, (M−^(t)Bu+1)⁺ 285, (M−Boc+1)⁺ 241; ¹HNMR=400 MHz (CDCl₃) δ: 9.60 (br s, 1H), 7.10 (m, 1H), 6.78 (m, 2H), 1.41(s, 9H).

B. 3-(2,4-Difluoro-benzyl)-3-methylaminomethyl-piperazine-1-carboxylicAcid tert-Butyl Ester

To a solution of the aldehyde of Example 198, Step A (340 mg, 1 mmol) indry DME (10 mL) was added about 250 mg MgSO₄ followed by methyl amine (1mL of a 2.0 M solution in MeOH, 2 equiv). The reaction was monitored byMS for the consumption of aldehyde and formation of the correspondingimine (+APcl (M+1)⁺ 354). Once imine formation was complete, NaOAc (820mg, 10 mmol) and NaCNBH₃ (248 mg, 4 mmol) were added and the mixture wasstirred at room temperature for 1 h. The mixture was filtered throughCelite® and the filtrate was concentrated. The resulting residue wastaken up in EtOAc (25 mL) and washed with 1 N NaOH and brine solutions,respectively. The organic phase was dried over MgSO₄ and concentrated todeliver the crude amine (306 mg). Purification by flash chromatography(SiO₂ gel, 3:1:0.2 EtOAc:Hexane:EtOH) delivered 210 mg (59%) of thediamine of Example 198, Step B: +APcl MS (M+1)⁺ 356, (M−^(t)Bu+1)⁺ 300,(M−Boc+1)⁺ 256; ¹H NMR=400 MHz (CDCl₃) δ: 7.21 (m, 1H), 6.81 (m, 2H),2.51 (br s, 3H), 1.42 (s, 9H).

C.8a-(2,4-Difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicAcid tert-Butyl Ester

To a solution of the diamine of Example 198, Step B (178 mg, 0.5 mmol)in CH₂Cl₂ (5 mL) was added triethylamine (0.13 mL, 1 mmol) andtriphosgene (148 mg, 0.5 mmol). The resulting solution was stirred atroom temperature for 1 h and then quenched with water (10 mL). The ureawas extracted with CH₂Cl₂, dried over MgSO₄ and concentrated to deliverthe crude product (187 mg). Purification by flash chromatography (SiO₂gel, 1:1, EtOAc:Hexane) delivered 156 mg (82%) of the urea of Example198, Step C: +APcl MS (M+1)⁺ 382, (M−^(t)Bu+1)⁺ 326, (M−Boc+1)⁺ 282.3;¹H NMR=400 MHz (CDCl₃) δ: 7.24 (m,1H), 6.81 (m, 2H), 2.67 (br s, 3H),1.48 (s, 9H).

D.(1-{1(R)-Benzyloxmethyl-2-[8a(S)-(2,4-difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

To a solution of the compound of Example 198, Step C (38 mg, 0.1 mmol)in EtOH (2 mL) was added 0.5 mL of conc. HCl at 0° C. The solution wasstirred for 1 h. Water (10 mL) was added and the resulting solution wasbasified to pH 14 with 1 N NaOH. The amine was extracted with CH₂Cl₂(3×10 mL) and the combined extracts were dried over MgSO₄ andconcentrated to deliver 27 mg of the urea: +APcl MS (M+1)⁺ 282. To asolution of the above urea (27 mg, 0.1 mmol) in EtOAc (5 mL) was addedtriethylamine (0.07 mL, 0.5 mmol), PPAA (0.035 mL, 0.1 mmol) and theacid of Example 2, Step 1 (38 mg, 0.1 mmol). The solution was stirred atroom temperature for 3 h. Water (10 mL) was added and the product wasextracted with EtOAc (3×15 mL). The combined extracts were dried overMgSO₄ and concentrated to provide a pale yellow oil. Purification byflash chromatography (SiO₂ gel, 3:1, EtOAc:hexanes) delivered 12 mg(19%) of the compound of Example 198, Step D (less polar diastereomer):+APcl MS (M+1)⁺ 644, (M−Boc+1)⁺ 544; ¹H NMR=400 MHz (CDCl₃) δ: 7.26 (m,6H), 6.91 (m, 2H), 2.63 (s, 3H), 1.38 (s, 9H).

E.2-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(2,4-difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,Hydrochloride

To a solution of the compound of Example 198, Step D (12 mg) in EtOH (2mL, 0° C.) was added conc. HCl (0.2 mL). The solution was stirred at 0°C. for 1 h and concentrated down to deliver 10 mg of Example 198, StepE: +APcl MS (M+1)⁺ 544; ¹H NMR=400 MHz (CD₃O) δ: 7.31 (br m, 6H), 6.83(m, 2H), 2.59 (br s, 3H), 1.56 (br s, 6H).

EXAMPLE 1992-Amino-N-{1(R)-1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-4-phenyl-butyl}-2-methyl-propionamide,Hydrochloride

A. 2(R)-Amino-5-phenyl-pentanoic acid(2(S)-hydroxy-1(S)-methyl-2-phenyl-ethyl)-methyl-amide

A solution of pseudoephedrine glycinamide (1.5 g, 6.75 mmol), preparedand used by the method of Myers et al. (J. Am. Chem. Soc. 1997, 119,656), and LiCl(1.71 g, 40.5 mmol) in THF (30 mL) was cooled to −78° C.and n-BuLi was added (13.16 mmol, 5.25 mL of a 2.5 M solution). Afterstirring for 20 min at −78° C., the reaction was warmed to 0° C. andstirred an additional 20 minutes. 3-Phenyl-1-bromopropane (1.3 mL, 7.42mmol) was added and the reaction was stirred for 2 h at 0° C. Aqueous 1N HCl (50 mL) and EtOAc (50 mL) were added, the organic phase wasseparated and extracted with 1 N HCl (50 mL). The aqueous extracts werecombined, cooled in an ice bath and slowly basified to pH 14 with 6 NNaOH. The product was extracted with CH₂Cl₂ (4×50 mL) and the combinedextracts were dried over MgSO₄ and concentrated to give a yellow oil.Purification by flash chromatography (SiO₂ gel, 92:4:4,CH₂Cl₂:MeOH:triethylamine) delivered 400 mg (78%) of the Product ofExample 199, Step A: +APcl MS (M+1)⁺ 341; ¹H NMR=400 MHz (CDCl₃) δ: 7.38(m, 10H), 5.26 (m, 1H), 4.15 (m, 1H), 3.86 (m, 1H), 2.36 (s, 3H).

B. 2(R)-Amino-5-phenyl-pentanoic Acid

A solution of the compound of Example 199, Step A (400 mg, 1.18 mmol) inwater (10 mL) was heated to reflux for 20 h. The reaction was dilutedwith water (20 mL) and extracted with CH₂Cl₂ (2×20 mL). The combinedorganic extracts were back extracted with water (2×20 mL) and thecombined aqueous extracts were concentrated down to a white solid. Thesolid was triturated with EtOH to remove residual pseudoephedrine anddeliver Example 199, Step B (135 mg, 60%): +APcl MS (M+1)⁺ 194.

C.2(R)-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-5-phenyl-pentanoicAcid

To a solution of the compound of Example 199, Step B (130 mg, 0.67 mmol)in dioxane: water (4:1, 5 mL) was added triethylamine (0.28 mL, 2 mmol)and Example 1, Step D (201 mg, 0.67 mmol). The mixture was stirred at45° C. for 16 h, diluted with EtOAc (20 mL) and water (10 mL) andacidified to pH 2 with HOAc. The organic phase was collected, washedwith saturated NaHCO₃ and brine solutions, dried over MgSO₄ andconcentrated to quantitatively give crude Example 199, Step C (298 mg):+APcl MS (M+1)⁺ 379, (M−^(t)Bu+1)⁺ 323, (M−Boc+1)⁺ 279; ¹H NMR=400 MHz(CDCl₃) δ: 7.21 (m, 2H), 7.14 (m, 3H), 4.51(m, 1H), 1.38 (s, 9H).

D.(1-{1(R)-[1,3-Dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-4-phenyl-butylcarbamoyl}-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

To a solution of the hydantoin of the Example 3a, Step A (164 mg, 0.5mmol) in EtOAc (5 mL) was added triethylamine (0.35 mL, 2.5 mmol), PPAA(0.16 mL, 0.5 mmol) and 16-C (189 mg, 0.5 mmol). The solution wasstirred at room temperature for 2 h. Water (10 mL) was added and theproduct was extracted with EtOAc (3×15 mL). The combined extracts weredried over MgSO₄ and concentrated to provide 382 mg of a pale yellowoil. Purification by flash chromatography (SiO₂ gel, 3:1, EtOAc:hexanes)delivered 73 mg of the compound of Example 199, Step D(diastereomerically pure): +APcl MS (M+1)⁺ 689, (M−^(t)Bu+1)³⁰ 633,(M−Boc+1)⁺ 589; ¹H NMR=400 MHz (CDCl₃) δ: 8.37 (m, 1H), 4.90 (br m, 3H),1.50 (s, 3H), 1.48 (s, 3H), 1.38 (s, 9H).

E.2-Amino-N-{1(R)-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-4-phenyl-butyl}-2-methyl-propionamide,Hydrochloride

To a solution of the compound of Example 199, Step D (73 mg) in EtOH (5mL, 0° C.) was added conc. HCl (0.5 mL). The solution was stirred at 0°C. for 1 h and concentrated down to deliver 68 mg of Example 199, StepE: +APcl MS (M+1)⁺ 589; ¹H NMR=400 MHz (CD₃OD) δ: 8.36 (d, 1H), 4.86 (brm, 3H), 1.44 (s, 3H), 1.42 (s, 3H).

EXAMPLE 2002-Amino-[2-(7a(R)-3a(S)-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

A. 1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic Acid Methyl Ester

To a solution of 1-benzyl-4oxo-piperidine-3-carboxylic acid methyl ester(5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride(60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride(2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed tostir for 14 h while warming to room temperature. The reaction mixturewas partitioned between EtOAc and saturated aqueous sodium bicarbonatesolution, the organic layer was removed and the aqueous layer was washedfour times with EtOAc. The combined organic layers were dried oversodium sulfate, filtered and concentrated under vacuum. Purification bysilica gel chromatography employing 0.5% MeOH/0.2% NH₄OH/CH₂Cl₂ as theeluant afforded the compound of Example 200, Step A as a pale yellow oil(5.89 g): +APcl MS (M+1)⁺ 338; ¹H NMR (400 MHz, CDCl₃) δ: 7.09-7.39(arom, series of m, 10H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20(d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H).

B. 1,3-Dibenzyl-4-methoxymethylene-piperidine-3-carboxylic Acid MethylEster

The material was prepared from the compound of Example 200, Step A (3.569, 11.0 mmol) as described in Example 8, Step A, affording the compoundof Example 200, Step B as a pale yellow oil after purification viasilica gel chromatography with 2-8% EtOAc/CH₂Cl₂ as the eluant (4.02 g):+APcl MS (M+1)⁺ 366; ¹H NMR (400 MHz, CDCl₃) d: 7.08-7.35 (arom, seriesof m, 10H), 5.94 (s, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.05 (d, 1H).

C. 1,3-Dibenzyl-4-formyl-piperidine-3-carboxylic Acid Methyl Ester

A solution of the compound of Example 200, Step B (3.02 g, 8.26 mmol) inTHF (40 mL) and 10% aqueous HCl solution (40 mL) was allowed to stir atroom temperature for 14 h. The solution was adjusted to pH 9 with 5NNaOH and extracted twice with CH₂Cl₂. The combined organic layers werewashed with a saturated aqueous brine solution, dried over Na₂SO₄,filtered and concentrated under vacuum. Purification by silica gelchromatography employing 3-5% EtOAc/CH₂Cl₂ as the eluant afforded thecompound of Example 200, Step C as a mixture of isomers (1.89 g): +APclMS (M+1)³⁰ 352; ¹H NMR (400 MHz, CDCl₃) δ: 9.82 and 9.81 (s, 1H),7.02-7.45 (arom, series of m, 10H), 3.64 and 3.60 (s, 3H).

D. 3a,5-Dibenzyl-2-methyl-octahydro-pyrrolo[3,4-c]pyridin-3-one

To a solution of the compound of Example 200, Step C (0.210 g, 0.60mmol) in dichloroethane (5 mL) in a resealable tube was added aceticacid (0.188 mL, 3.28 mmol), methyl amine (2.0 M in MeOH, 1.64 mL, 3.28mmol) and NaB(OAc)₃H (0.951 g, 4.48 mmol), the tube was sealed and thereaction mixture was heated to 70° C. for 30 h. The reaction mixture waspartitioned between CH₂Cl₂ and saturated aqueous sodium bicarbonatesolution. The organic layer was removed and the aqueous layer was washedtwice with CH₂Cl₂, the combined organic layers were washed with asaturated aqueous brine solution, dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by silica gel chromatographyemploying 5-30 20% EtOAc/CH₂Cl₂ as the eluant afforded the less polarisomer of Example 200, Step D (0.034 g) as well as the more polar isomer(0.046 g). Example 200, Step D less polar isomer: +APcl MS (M+1)⁺ 335;¹H NMR (400 MHz, CDCl₃) δ: 7.03-7.37 (arom, series of m, 10H), 3.54 (m,2H), 3.24 (m, 1H), 2.70 (s, 3H). More polar isomer: +APcl MS (M+1)⁺ 335;¹H NMR (400 MHz, CDCl₃) δ: 7.15-7.33 (arom, series of m, 10H), 3.59 (d,1H), 3.43 (d, 1H), 2.74 (s, 3H).

E. 3a-Benzyl-2-methyl-octahydro-pyrrolo[3,4-c]pyridin-3-one

To a solution of the compound of Example 200, Step D (0.034 g, 0.10mmol) in acetic acid (18 mL) was added a slurry of palladium on carbon(10% by weight, 0.030 g) in H₂O (2 mL). The reaction mixture was shakenunder 50 psig hydrogen for 24 h, an additional aliquot of palladium oncarbon (0.030 g) was introduced and the reaction was continued under 50psig hydrogen for another 24 h. The reaction mixture was filteredthrough a bed of Celite® with the aid of MeOH, concentrated undervacuum, and the residue was partitioned between CH₂Cl₂ and H₂O at pH 9.The organic layer was removed and the aqueous layer was washed twicewith CH₂Cl₂, the organic layers were combined and washed with asaturated aqueous brine solution, dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by silica gel chromatographyemploying 3% MeOH/0.2% NH₄OH/CH₂Cl₂ as the eluant afforded the compoundof Example 200, Step E (0.019 g): +APcl MS (M+1)⁺ 245; ¹H NMR (400 MHz,CDCl₃) δ: 7.10-7.24 (arom, series of m, 5H), 3.21 (m, 1H), 2.71 (s, 3H).

F.{1-[2-(7a(R)-3a(S)-Benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

To a solution of the compound of Example 200, Step E (0.019 g, 0.078mmol), the acid of Example 2, Step 1 (0.045 g, 0.12 mmol) and Et₃N(0.045 mL, 0.31 mmol) in EtOAc (1 mL) at 0° C. was added PPAA (50%solution in EtOAc, 0.093 mL, 0.16 mmol). After 24 h of stirring at roomtemperature, additional 2-I (0.015 g, 0.039 mmol) and PPAA (0.045 mL,0.078 mmol) were added and stirring was continued at room temperaturefor 24 h. The reaction mixture was partitioned between EtOAc andsaturated aqueous sodium bicarbonate solution, the organic layer wasremoved and the aqueous layer was washed twice with EtOAc. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under vacuum. Purification by silica gelchromatography employing EtOAc as the eluant afforded the less polarisomer of Example 200, Step F (0.005 g), as well as a mixture of the twoisomers (0.028 g). Example 200, Step F less polar isomer: +APcl MS(M+1)⁺ 607; ¹H NMR (400 MHz, CDCl₃) δ: 7.03-7.32 (arom, series of m,10H), 5.27 (m, 1H), 4.48 (m, 2H), 2.69 (s, 3H), 1.35 (s, 9H).

G.2-Amino-N-[2-(7a(R)-3a(S)-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,Hydrochloride

The compound of Example 200, Step F (0.005 g, 0.009 mmol) wasdeprotected as described in General Procedure C to provide the compoundof Example 200, Step G as the HCl salt (0.004 g). Example 200, Step G:+APcl MS (M+1)⁺ 507; ¹H NMR (400 MHz, CD₃OD) δ: 7.10-7.32 (arom, seriesof m, 10H), 5.23 (m, 1H), 2.73 (s, 3H), 1.56 (m, 6H).

EXAMPLE 2012-Amino-N-[2-(8a(S*)-benzyl-7(S*)-methyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide

A. 3-Benzyl-3-(2-methoxycarbonyl-vinyl)-piperazine-1-carboxylic Acidtert-Butyl Ester

To a THF (1 mL) solution of NaHMDS at 0° C. was added trimethylphosphonoacetate (0.18 mL, 1.1 mmol), dropwise. After stirring for 1hour, a THF (1 mL) solution of crude3-benzyl-3-formyl-piperazine-1-carboxylic acid tert-butyl ester (0.34mg, 0.92 mmol), prepared analogous to the compound of Example 198, StepA, was added and the reaction was allowed to warm to room temperature.After stirring for 16 hours, the product was isolated by extraction fromwater with EtOAc (2×) and methylene chloride (2×). The combined extractswere washed with brine, dried (MgSO₄) and concentrated. The product wasthen purified by silica gel chromatography using methylene chloride,then 5% MeOH in methylene chloride as eluents to afford a 7:3 E:Zmixture of olefins of the compound of Example 201, Step A (0.38 g, 81%),where the Z isomer had lactamized: +APcl MS (M+1, ester)⁺ 361,(M−^(t)Bu+1, ester)⁺ 305, (M−^(t)Bu+1, lactam)⁺ 273, (M−BOC+1, ester)⁺261, (M−BOC+1, lactam)⁺ 229; ¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.05 (arom,series of m, 5H), 6.91 (lactam olefin, d, 0.3H), 6.75 (ester olefin, d,0.7H), 6.09 (lactam olefin, d, 0.3H), 5.88 (ester olefin, d, 0.7H), 3.71(ester Me, s, 2.1H), 1.47 (BOC, s, 9H).

B. 3-Benzyl-3-(2-methoxycarbonyl-ethyl)-piperazine-1-carboxylic Acidtert-Butyl Ester

A methanolic solution of the compound of Example 201, Step A washydrogenated (40 psi) in a Parr shaker over 10% Pd-C (35 mg). After 17hours, the reaction was filtered through a pad of Celite® and thenconcentrated to give yellowish solid of the compound of the compound ofExample 201, Step B (153 mg, 90%) which was a 1:2 mixture of ester andlactam: +APcl MS (M+1, ester)⁺ 363, (M+1, lactam)⁺ 331; ¹H NMR (400 MHz,CDCl₃) δ: 7.25-7.05 (arom, series of m, 5H), 3.54 (ester Me, s, 1H),1.44 (lactam BOC, s, 6H),1.37 (ester BOC, s, 3H).

C. 8a-Benzyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic Acidtert-Butyl Ester

To a methanolic (4 mL) solution of the compound of Example 201, Step Bwas added solid K₂CO₃. The mixture was refluxed for 30 minutes, thenconcentrated and extracted from saturated aqueous NH₄Cl with methylenechloride to give lactam of Example 201, Step C as a yellowish solid(70.6 mg, 50%): +APcl MS (M+1)⁺ 331, (M−^(t)Bu+1)⁺ 275, (M−BOC+1)⁺ 231;¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.05 (arom, series of m, 5H), 4.06 (d,1H) , 3.06 (d, 1H), 2.67 (d, 1H), 2.07 (m, 2H), 1.49 (BOC, s, 6H).

D.8a(S*)-Benzyl-7(S*)-methyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicAcid tert-Butyl Ester

To a THF (0.4 mL) solution of lithium diisopropylamide (2.0 mmol) at−78° C. was added the compound of Example 201, Step C (192 mg, 0.58mmol) in 1,2-dimethoxyethane (3 mL). After 20 minutes, methyl iodide(0.36 mL, 5.8 mmol) was added dropwise and the reaction was stirred anadditional 1 hour. The reaction was quenched at −78° C. with brine, andthe reaction was then extracted with EtOAc (3×), dried (MgSO₄), andconcentrated. The product was then purified by silica gel chromatographyusing 7:3 to 1:1 hexanes/EtOAc as eluents to afford the dimethyl lactam(78 mg, 37%),8a-benzyl-7,7-dimethyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester, the (R*,S*) methyl lactam (68 mg, 34%), followedby the (S*,S*) methyl lactam of Example 201, Step D (58 mg, 29%).Dimethyl lactam: +APcl MS (M+1)⁺ 359, (M−^(t)Bu+1)³⁰ 303, (M−BOC+1)⁺259; ¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.10 (arom, series of m, 5H), 3.18(td, 1H), 3.0 (d, 1H), 2.0 (d, 1H), 1.49 (BOC, s, 9H), 1.13 (Me, s, 3H),0.66 (Me, br s, 3H). (R*,S*) lactam: +APcl MS (M+1)³⁰ 345, (M−^(t)Bu+1)⁺289, (M−BOC+1)⁺ 245; ¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.05 (arom, seriesof m, 5H), 3.04 (d, 1H), 2.66 (d, 1H), 2.31 (dd, 1H), 1.49 (BOC, s, 9H),1.99 (Me, d, 3H). The (S*, S*) lactam of Example 201, Step D: +APcl MS(M+1)³⁰ 345, (M−^(t)Bu+1)⁺ 289, (M−BOC+1)⁺ 245; ¹H NMR (400 MHz, CDCl₃)δ: 7.30-7.05 (arom, series of m, 5H), 2.97 (d, 1H), 2.81 (d, 1H), 2.40(m, 1H), 1.48 (BOC, s, 9H), 0.73 (Me, br s, 3H).

E.{1-[2-(8a(S*)-Benzyl-7(S*)-methyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

The compound of Example 201, Step D (58 mg, 0.17 mmol) was deprotectedas described in General Procedure C to provide the secondary amine asthe HCl salt: +APcl MS (M+1)⁺ 245; ¹H NMR (400 MHz, CD₃OD) d: 7.15-7.35(arom, series of m, 5H), 4.26 (dd, 1H), 3.17 (d, 1H), 2.78 (d, 1H), 2.02(dd, 1H), 1.76 (dd, 1H), 0.46 (Me, d, 3H).

To a solution of the crude amine, the acid of Example 2, Step 1 (96 mg,0.25 mmol) and Et₃N (0.16 mL, 1.2 mmol) in EtOAc (1 mL) at 0° C. wasadded PPAA (50% solution in EtOAc, 0.16 mL, 0.27 mmol). After 16 h ofstirring at room temperature, the reaction mixture was extracted fromsaturated aqueous sodium bicarbonate with EtOAc, and the combinedextracts dried (MgSO₄) and concentrated. Purification by silica gelchromatography employing 7:3 EtOAc/hexanes, then EtOAc, then 19:1EtOAc/MeOH as eluants afforded the less polar isomer of Example 201,Step E (29 mg, 28%), the more polar isomer (41 mg, 40%), as well as somemixed fractions. Less polar isomer of Example 201, Step E: +APcl MS(M+1)⁺ 607, (M−BOC+1)⁺ 507; ¹H NMR (400 MHz, CDCl₃) δ: 7.35-6.80 (arom,series of m, 10H), 4.68 (d, 1H), 4.47 (AB_(q), 2H), 2.63 (d, 1H), 0.91(Me, m, 1.5H), 0.63 (Me, d, 1.5H). More polar isomer: +APcl MS (M+1)³⁰607, (M−BOC+1)⁺ 507; ¹H NMR (400 MHz, CDCl₃) δ: 7.70-6.85 (arom, seriesof m, 10H), 4.65 (d, 1H) , 4.50 (½Ab_(q), 1H), 4.41 (½Ab_(q), 1H) 1H),2.59 (d, 1H), 0.87 (Me, m, 1.5H), 0.63 (Me, d, 1.5H).

F.2-Amino-N-[2-(8a(S*)-benzyl-7(S*)-methyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide

The compound of Example 201, Step E (29 mg, 0.048 mmol) was deprotectedas described in General Procedure C to provide, after trituration withether, the compound of Example 201, Step F as its HCl salt (23 mg, 88%):+APcl MS (M+1)⁺ 507; ¹H NMR (400 MHz, CD₃OD) δ: 7.40-6.90 (arom, seriesof m, 10H), 4.59 (d, 1H), 4.54 (s, 2H), 4.04 (d, 1H), 2.71 (d, 1H), 2.57(d, 1H).

EXAMPLE 2022-Amino-N-[1(R)-benzyloxymethyl-2-oxo-2-(6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-ethyl]-2-methyl-propionamide

A.8-Hydroxy-6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicAcid tert-Butyl Ester

To a 0° C. methanolic (5 mL) solution of6,8-dioxo-8a-pyridin-2ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester (203 mg, 0.59 mmol), prepared analogously to thecompound of Example 6, Step D but used crude, small portions of sodiumborohydride were added until TLC indicated starting material wasconsumed. The reaction was then quenched with water, and then extractedfrom saturated aqueous NaHCO₃ with EtOAc. The combined extracts werewashed with brine, dried (MgSO₄), and concentrated. Purification bysilica gel chromatography employing 3:7 then 2:1 EtOAc/hexanes aseluants afforded the alcohol of Example 202, Step A (95 mg, 38%): +APclMS (M+1)⁺ 348, (M−^(t)Bu+1)⁺ 292; ¹H NMR (400 MHz, CDCl₃) δ: 8.45 (arom,d, 1H), 7.70-7.07 (arom, series of m, 3H), 4.00, (dd, 1H), 3.28 (AB_(q),2H), 2.64 (dd, 1H), 1.40 (BOC, s, 9H).

B.6-Oxo-8a-pyridin-2-ylmethyl-3,4,6,8a-tetrahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylicAcid tert-Butyl Ester

To a solution of the compound of Example 202, Step A (240 mg, 0.69 mmol)and triethylamine (0.29 mL, 2.1 mmol) at 0° C. in methylene chloride (10mL) was added methanesulfonyl chloride (0.11 mL, 1.4 mmol), dropwise.After stirring 18 hours, the solvent was removed under vacuum and wasreplaced with toluene (15 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5mL, 3.3 mmol) was added, and the reaction was heated for 4 hours at 100°C. The material was extracted from water with EtOAc, and the combinedextracts were dried (MgSO₄) and concentrated. Purification by silica gelchromatography employing chloroform then 19:1 chloroform/MeOH as eluantsafforded the compound of Example 202, Step B (147 mg, 65%): +APcl MS(M+1)⁺ 330, (M−^(t)Bu+1)⁺ 274; ¹H NMR (400 MHz, CDCl₃) δ: 8.43 (arom, d,1H), 7.55-6.90 (series of m, 4H), 6.00, (olefin, d, 1H), 3.09 (d, 1H),1.42 (BOC, s, 9H).

C.6-Oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicAcid tert-Butyl Ester

To a −78° C. solution of the compound of Example 202, Step B in THF (15mL) was added lithium tri-sec-butylborohydride (1 M in THF, 1.44 mL),the reaction was stirred 10 minutes and then allowed to warm to roomtemperature. After 4 hours, the reaction was extracted from saturatedaqueous NaHCO₃ with EtOAc. The combined extracts were washed with brine,dried (MgSO₄), and concentrated to afford the compound of Example 202,Step C (320 mg, quantitative): +APcl MS (M+1)⁺ 332, (M−^(t)Bu+1)⁺ 276;¹H NMR (400 MHz, CDCl₃) δ: 8.40 (arom, m, 1H), 7.55 (arom, m, 1H),7.15-7.00 (series of m, 2H), 3.99 (br d, 1H), 2.85 (d, 1H), 1.43 (BOC,s, 9H).

D. 8a-Pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-6-one

The compound of Example 202, Step C (11 mg, 0.033 mmol) was deprotectedas described in General Procedure C to provide the secondary amine ofExample 202, Step D as the HCl salt (9 mg, quantitative): +APcl MS(M+1)⁺ 232; ¹H NMR (400 MHz, CD₃OD) δ: 8.87 (arom, d, 1H), 8.59 (arom,t, 1H), 8.06 (arom, t, 1H), 7.96 (arom, d, 1H), 4.32 (dd, 1H), 3.94 (d,1H), 3.74 (d, 1H), 1.59 (m, 1H).

E.{1-[1(R)-Benzyloxmethyl-2-oxo-2-(6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-ethylcarbamoyl]-1-methyl-ethyl}-carbamicAcid tert-Butyl Ester

To a solution of the compound of Example 202, Step D (330 mg, 1.54mmol), the acid of Example 2, Step 1 (785 mg, 2.1 mmol) and Et₃N (1.1mL, 7.7 mmol) in EtOAc (10 mL) at 0° C. was added PPAA (50% solution inEtOAc, 0.88 mL, 2.10 mmol). After 2 h, the reaction mixture wasextracted from saturated aqueous sodium bicarbonate with EtOAc, and thecombined extracts washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography employing EtOAc, then 19:1EtOAc/MeOH as eluants afforded the compound of Example 202, Step E (250mg, 29%) as a 1:1 mixture of diastereomers: +APcl MS (M+1)⁺ 594,(M−BOC+1)⁺ 494.

F.2-Amino-N-[1(R)-benzyloxymethyl-2-oxo-2-(6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-ethyl]-2-methyl-propionamide

Compound of Example 202, Step E (12 mg, 0.020 mmol) was deprotected asdescribed in General Procedure C to provide, after trituration withether, Example 202, Step F as its HCl salt (5 mg, 50%): +APcl MS (M+1)⁺494; ¹H NMR (400 MHz, CD₃OD) δ: 8.90-7.15 (arom, series of m, 9H), 5.31(m, 0.5H), 5.15 (m, 0.5H), 2.86 (d, 0.5H), 2.77 (d, 0.5H), 1.60 (Me, m,6H).

EXAMPLE 2032-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide

A.8a-(4-Fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicAcid tert-Butyl Ester

To a DMSO (2 mL) solution of the compound of Example 6, Step D was addedNaH (60% dispersion in mineral oil, 33 mg, 0.83 mmol) was added methyliodide (0.017 mL, 0.28 mmol), the mixture was stirred for 1 hour, andthen an additional portion of methyl iodide (0.017 mL, 0.28 mmol) wasadded. After stirring 3 days, the reaction mixture was extracted fromsaturated aqueous sodium bicarbonate with EtOAc, and the combinedextracts washed with brine, dried (MgSO₄) and concentrated. Purificationby silica gel chromatography employing hexanes, then 1:1 EtOAc/hexanesas eluants afforded the compound of Example 203, Step A (20 mg, 29%):+APcl MS (M−^(t)Bu+1)⁺ 335, (M−BOC+1)³⁰ 291; ¹H NMR (400 MHz, CDCl₃) δ:6.93 (arom, m, 4H), 4.40 (dd, 1H), 1.50 (BOC, s, 9H), 1.13 (Me, s, 3H),0.26 (Me, s, 3H).

B.8a-(4-Fluoro-benzyl)-7,7-dimethyl-tetrahydro-pyrrolo[1,2-a]pyrazine-6,8-dione

The compound of Example 203, Step A (20 mg, 0.061 mmol) was deprotectedas described in General Procedure C to provide the secondary amine ofExample 203, Step B as the HCl salt (17 mg, 85%): +APcl MS (M+1)⁺ 291;¹H NMR (400 MHz, CD₃OD) δ: 7.04 (arom, m, 4H), 4.56 (dd, 1H), 3.50 (d,1H), 3.07 (d, 1H), 1.16 (Me, s, 3H), 0.16 (Me, s, 3H).

C.(1-{1(R)-Benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

To a solution of the compound of Example 203, Step B (17 mg, 0.052mmol), the acid of Example 2, Step 1 (24 mg, 0.062 mmol) and EtaN (0.036mL, 0.26 mmol) in EtOAc (0.5 mL) at 0° C. was added PPAA (50% solutionin EtOAc, 0.88 mL, 2.10 mmol). After 3 h, the reaction mixture wasextracted from saturated aqueous sodium bicarbonate with EtOAc, and thecombined extracts washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography employing hexanes, then 1:1EtOAc/hexanes as eluants afforded the less polar isomer of Example 263,Step C (4 mg, 28%) followed by the more polar isomer (6 mg, 43%). Lesspolar isomer of Example 203, Step C: +APcl MS (M−BOC+1)⁺ 553; ¹H NMR(400 MHz, CDCl₃) δ: 7.40-6.80 (arom, series of m, 9H), 4.85 (d, 1H),4.47 (Ab_(q), 2H), 2.51 (d, 1H), 1.12 (Me, s, 3H), 0.24 (Me, s, 3H).More polar isomer: +APcl MS (M−BOC+1)⁺ 553; ¹H NMR (400 MHz, CDCl₃) δ:7.35-6.50 (arom, series of m, 9H), 4.85 (d, 1H) , 4.55 (½Ab_(q), 1H) ,4.42 (½Ab_(q), 1H), 2.87 (d, 1H), 2.45 ( 3H), 0.15 (Me, s, 3H).

D.2-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide

The compound of Example 203, Step C (4 mg, 0.006 mmol) was deprotectedas described in General Procedure C to provide, after trituration withether, the compound of Example 201, Step F as its HCl salt (3 mg, 83%):+APcl MS (M+1)⁺ 553; ¹H NMR (400 MHz, CD₃OD) δ: 7.40-6.90 (arom, seriesof m, 9H), 5.16 (t, 1H), 4.69 (d, 1H), 4.54 (s, 2H), 2.85 (t, 1H), 1.56(ala Me, s, 6H), 1.12 (Me, s, 3H), 0.20 (Me, s, 3H).

The following abbreviations and notations are used in the Tables below.

Abbreviation:

Me—methyl

Et—ethyl

Ph—phenyl

Pyr—pyridyl

c-Pr—cyclopropyl

A=Mass Spec. Method is ⁻APcl

B=Mass Spec. Method is PB

C=Mass Spec. Method is ⁺APcl

EXAMPLES 204-206

The compounds of examples 204-206 were synthesized in a manner analogousto the procedures described for Example 9 using the appropriate startingmaterials.

Example R² R¹ R″ isomer MS 204 Me CH₂-2-Pyr OCH₂Ph d1, 2 510^(C) 205 EtCH₂-2-Pyr OCH₂Ph d1, 2 524^(C) 206 Et CH₂-2-Pyr OCH₂Ph d3, 4 524^(C)

EXAMPLES 207-230

The compounds of examples 207-230 were synthesized in a manner analogousto procedures described for Example 200 using the appropriate startingmaterials.

Example R² R¹ R″ isomer MS 207 Me CH₂Ph OCH₂Ph d1 507^(C) 208 Me CH₂PhOCH₂Ph d2 507^(C) 209 Me CH₂Ph OCH₂Ph d4 507^(C) 210 Me CH₂Ph OCH₂Ph d3,4 507^(C) 211 c-Pr CH₂Ph OCH₂Ph d1, 2 533^(C) 212 c-Pr CH₂Ph OCH₂Ph d3533^(C) 213 c-Pr CH₂Ph OCH₂Ph d3, 4 533^(C) 214 Et CH₂Ph OCH₂Ph d1, 2521^(C) 215 Et CH₂Ph OCH₂Ph d3, 4 521^(C) 216 Me CH₂-4-F—Ph OCH₂Ph d3, 4525^(C) 217 Me CH₂-4-F—Ph OCH₂Ph d1, 2 525^(C) 218 CF₃CH₂ CH₂Ph OCH₂Phd3 575^(C) 219 CF₃CH₂ CH₂-4-F—Ph OCH₂Ph d3, 4 593^(C) 220 CF₃CH₂ CH₂PhOCH₂Ph d4 575^(C) 221 CF₃CH₂ CH₂-4-F—Ph OCH₂Ph d1, 2 593^(C) 222 CF₃CH₂CH₂Ph OCH₂Ph d1, 2 575^(C) 223 Et CH₂-4-F—Ph OCH₂Ph d1, 2 539^(C) 224 EtCH₂-4-F—Ph OCH₂Ph d3 539^(C) 225 Et CH₂-4-F—Ph OCH₂Ph d4 539^(C) 226 BnCH₂-4-F—Ph OCH₂Ph d1, 2, 601^(C) 3, 4 227 Me CH₂-2-Pyr OCH₂Ph d1, 2508^(C) 228 Et CH₂-2-Pyr OCH₂Ph d1, 2 522^(C) 229 H CH₂Ph OCH₂Ph d1, 2493^(C) 230 H CH₂Ph OCH₂Ph d3, 4 493^(C)

EXAMPLE 231

The compound of Example 231 was synthesized in a manner analogous toprocedures described for Example 203 using the appropriate startingmaterials.

Example R² R¹ R″ isomer MS 231 Me CH₂-2-F—Ph OCH₂Ph d2 553^(C)

EXAMPLES 232-238

The compounds of examples 232-238 were synthesized in a manner analogousto procedures described for Examples 201 and 202 using the appropriatestarting materials.

Example R² R³ R¹ R″ isomer MS 232 H H CH₂Ph OCH₂Ph d1 493^(C) 233 H HCH₂Ph OCH₂Ph d2 493^(C) 234 H Me CH₂Ph OCH₂Ph d2 507^(C) 235 H Me CH₂PhOCH₂Ph d3 507^(C) 236 H Me CH₂Ph OCH₂Ph d4 507^(C) 237 Me Me CH₂PhOCH₂Ph d1 521^(C) 238 Me Me CH₂Ph OCH₂Ph d2 521^(C)

EXAMPLES 239-240

The compounds of Examples 239-240 were synthesized in a manner analogousto procedures described for Example 199 using the appropriate startingmaterials.

Example R′ R¹ R″ isomer MS 239 CF₃CH₂ CH₂-2-Pyr CH═CH-2,4-di-F—Ph d1622^(C) 240 CF₃CH₂ CH₂-2-Pyr CH═CH-4-Cl—Ph d1 620^(C)

EXAMPLES 241-251

The compounds of Examples 241-251 were synthesized in a manner analogousto procedures described for Examples 2, 197 and 198 using theappropriate starting materials.

Example R² R¹ R″ isomer MS 241 CF₃CH₂ CH₂-2,4-di-F—Ph OCH₂Ph d1, 2612^(C) 242 CH₂Ph CH₂-2,4-di-F—Ph OCH₂Ph d1 620^(C) 243 CH₂PhCH₂-2,4-di-F—Ph OCH₂Ph d2 620^(C) 244 CF₃CH₂ CH₂Ph OCH₂Ph d1 576^(C) 245CF₃CH₂ CH₂Ph OCH₂Ph d2 576^(C) 246 CF₃CH₂ CH₂-2-Pyr OCH₂Ph d1 577^(C)247 CH₂Ph CH₂Ph OCH₂Ph d1 584^(C) 248 CH₂Ph CH₂Ph OCH₂Ph d2 584^(C) 249Me CH₂-2-Pyr OCH₂Ph d1, 2 509^(C) 250 Et CH₂-2-Pyr OCH₂Ph d1, 2 523^(C)251 Bn CH₂-2-Pyr OCH₂Ph d1, 2 585^(C)

What is claimed is:
 1. A compound of the formula

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, wherein HET is a heterocyclic moiety selected fromthe group consisting of

Q is a covalent bond or CH₂; X is CH₂, C═CH₂ or C═O; Y isCH_(2, O or NR) ²; Z is SO₂; R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)A¹, —(CH₂)_(q)OX⁶—(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶) (X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl; where A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and  where the alkyl and cycloalkylgroups in the definition of R¹ are optionally substituted with(C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, or 1, 2 or 3 fluoro groups;  q is1 or 2;  t is 1 or 2;  said (CH₂)_(q) group and (CH₂)_(t) group in thedefinition of R¹ are optionally independently substituted with hydroxy,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)m(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkylgroups; R² is hydrogen, (C₁-C₅)alkyl or (C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition ofR² are optionally substituted with fluoro groups;  R³ isphenyl-CH₂—O—CH₂—, phenyl-CH₂—S—CH₂—, pyridyl-CH₂—O—CH₂—,thienyl-CH₂—O—CH₂—, thiazolyl-CH₂—O—CH₂—, phenyl-(CH₂)₃— or3-indolyl-CH₂—; where the carbon atom bearing the substituent R³ is ofthe (R) configuration; where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,CL, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; R⁴ is hydrogen; X⁴ is hydrogen;

 where a and b are each 0;  X⁵ and X^(5a) are each methyl;  Z¹ is abond; R⁷ and R⁸ are each hydrogen.
 2. A compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 1 wherein Q is a covalent bond; X is CH₂; andY is CH₂ or NR².
 3. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 2wherein Y is CH₂.
 4. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 3wherein R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; and R³ is selected from the group consistingof 3-indolyl-CH₂—, phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 5. A compound ora prodrug of such compound or a pharmaceutically acceptable salt of thecompound or a prodrug according to claim 4 where the compound is the3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer or the3a(S),1(R) diastereomer of2-amino-N-[2-(3a-benzyl-1,1-dioxo-hexahydro-1thia-5,7a-diaza-inden-5yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.6. A compound according to claim 1 wherein Q is a covalent bond; X isC═O; and Y is NR².
 7. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1wherein Q is a covalent bond; X is C═O; Y is NR²; R¹ is hydrogen; and R³is selected from the group consisting of phenyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, phenyl-(CH₂)₃—, 3-indolyl-CH₂— andthiazolyl-CH₂—O—CH₂—, where the a groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of methylenedioxy, F,Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 8. A pharmaceutical compositionwhich comprises a pharmaceutically acceptable carrier and an effectiveamount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1.9. A pharmaceutical composition useful for increasing the endogenousproduction or release of growth hormone in a human or other animal whichcomprises a pharmaceutically acceptable carrier, an effective amount ofa compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 1 and a growthhormone secretagogue selected from the group consisting of GHRP-6,Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2and B-HT920 or an analog thereof.
 10. A method for increasing levels ofendogenous growth hormone in a human or other animal which comprisesadministering to such human or animal an effective amount of a compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 11. A method for treating orpreventing osteoporosis and/or frailty which comprises administering toa human or other animal in need of such treatment or prevention anamount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in treating or preventing osteoporosis and/orfrailty.
 12. A method for treating or preventing diseases or conditionswhich may be treated or prevented by growth hormone which comprisesadministering to a human or other animal in need of such treatment orprevention an amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in promoting release of endogenous growth hormone.13. A method of claim 12 wherein said condition is a sleep disorder. 14.A method according to claim 12 wherein the disease or condition iscongestive heart failure, frailty associated with aging or obesity. 15.A method according to claim 14 wherein the disease or condition iscongestive heart failure.
 16. A method according to claim 14 wherein thedisease or condition is frailty associated with aging.
 17. A method foraccelerating bone fracture repair, attenuating protein catabolicresponse after a major operation, reducing cachexia and protein loss dueto chronic illness, accelerating wound healing, or accelerating therecovery of bum patients or patients having undergone major surgery,which method comprises administering to a mammal in need of suchtreatment an amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in promoting release of endogenous growth hormone.18. A method according to claim 17 wherein the method is foraccelerating the recovery of patients having undergone major surgery.19. A method according to claim 17 wherein the method is foraccelerating bone fracture repair.
 20. A method for improving musclestrength, mobility, maintenance of skin thickness, metabolic homeostasisor renal homeostasis, which method comprises administering to a human orother animal in need of such treatment an amount of a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 1 which is effective in promotingrelease of endogenous growth hormone.
 21. A method for the treatment orprevention of osteoporosis and/or frailty which comprises administeringto a human or other animal with osteoporosis and/or frailty effectiveamounts of a bisphosphonate compound and a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 22. A method for the treatment ofosteoporosis and/or frailty according to claim 21 wherein thebisphosphonate compound is alendronate.
 23. A method for the treatmentof osteoporosis and/or frailty according to claim 21 wherein thebisphosphonate compound is ibandronate.
 24. A method for the treatmentor prevention of osteoporosis and/or frailty which comprisesadministering to a human or other animal with osteoporosis and/orfrailty effective amounts of estrogen or Premarin® and a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 1 and, optionally, progesterone.25. A method for the treatment of osteoporosis and/or frailty whichcomprises administering to a human or other animal with osteoporosisand/or frailty effective amounts of calcitonin and a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 26. A method to increase IGF-1levels in a human or other animal deficient in IGF-1 which comprisesadministering to a human or other animal with IGF-1 deficiency acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 27. A methodfor the treatment of osteoporosis and/or frailty which comprisesadministering to a human or other animal with osteoporosis and/orfrailty effective amounts of an estrogen agonist or antagonist and acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 28. A methodaccording to claim 27 wherein the estrogen agonist or antagonist istamoxifen, droloxifene, raloxifene or idoxifene.
 29. A method accordingto claim 27 wherein the estrogen agonist or antagonist iscis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline.30. A method for enhancing growth and improving carcass quality of ananimal other than humans which comprises administering to said animal aneffective amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1.31. A method for enhancing feed efficiency in an animal other thanhumans which comprises administering to said animal an effective amountof a compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 32. A methodfor increasing milk production in a female mammal which comprisesadministering to said female mammal an effective amount of a compound ora stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 33. A method for increasingpiglet number, increasing pregnancy rate in sows, increasing viabilityof piglets, increasing weight of piglets or increasing muscle fiber sizein piglets which comprises administering to a sow or piglet an effectiveamount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1.34. A method for increasing muscle mass, which method comprisesadministering to a human or other animal in need of such treatment anamount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in promoting release of endogenous growth hormone.35. A method for promoting growth in growth hormone deficient childrenwhich comprises administering to a growth hormone deficient child acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 1 which iseffective in promoting release of endogenous growth hormone.
 36. Amethod for the treatment or prevention of congestive heart failure,obesity or frailty associated with aging, which comprises administeringto a human or other animal in need thereof effective amounts of afunctional somatostatin antagonist and a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 37. A method according to claim 36 whereinthe functional somatostatin antagonist is an alpha-2 adrenergic agonistand the other animal is a dog, cat or a horse.
 38. A method according toclaim 36 wherein the alpha-2 adrenergic agonist is clonidine, xylazineor medetomidine.
 39. A method for treating insulin resistance in amammal, which comprises administering to said mammal an effective amountof a compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 40. A methodfor increasing the endogenous production or release of growth hormone ina human or other animal which comprises administering effective amountsof a compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 1 and a growthhormone secretagogue selected from the group consisting of GHRP-6,Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2and B-HT920 or an analog thereof.
 41. A pharmaceutical compositionuseful for treating or preventing osteoporosis and/or frailty whichcomprises a pharmaceutically acceptable carrier, an amount of abisphosphonate compound and an amount of a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 42. A pharmaceutical composition usefulfor treating or preventing osteoporosis and/or frailty which comprises apharmaceutically acceptable carrier, an amount of estrogen or Premarin®,an amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1and, optionally, an amount of progesterone.
 43. A pharmaceuticalcomposition useful for treating osteoporosis and/or frailty whichcomprises a pharmaceutically acceptable carrier, an amount of calcitoninand an amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1.44. A pharmaceutical composition useful for treating preventingcongestive heart failure, obesity or frailty associated with aging,which comprises a pharmaceutically acceptable carrier, an amount of analpha-2 adrenergic agonist and an amount of a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 45. A pharmaceutical compositionaccording to claim 44 wherein the alpha-2 adrenergic agonist isclonidine, xylazine or medetomidine.
 46. A method for increasing levelsof endogenous growth hormone, which comprises administering to a humanor other animal in need thereof effective amounts of a functionalsomatostatin antagonist and a compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 47. A method according to claim 39 whereinthe condition associated with insulin resistance is type I diabetes,type II diabetes, hyperglycemia, impaired glucose tolerance or aninsulin resistant syndrome.
 48. A method according to claim 39 whereinthe condition associated with insulin resistance is associated withobesity or old age.